Peptide inhibitors of transcription factor aggregation

ABSTRACT

This invention relates to materials, such as peptides, and methods to inhibit the aggregation transcription factors, for example p53 inhibitors, p63 inhibitors and p73 inhibitors. More specifically, the invention relates to cancer chemotherapeutics. More specifically, the invention provides pharmaceutical compositions and methods of treating cancer with certain peptides.

FIELD OF THE INVENTION

This invention relates to the field of transcription factors, forexample p53, p63 and p73. More specifically, the invention relates tocancer chemotherapeutics that modulate the activity of a transcriptionfactor, e.g., by modulating aggregation of the transcription factor.More specifically, the invention provides pharmaceutical compositionsand methods of treating cancer with certain peptides.

BACKGROUND

p53 is a tumor suppressor and transcription factor that responds tocellular stress by activating the transcription of numerous genesinvolved in cell cycle arrest, apoptosis and DNA repair. Unlike normalcells, which have infrequent cause for p53 activation, tumor cells areunder constant cellular stress from various insults including hypoxiaand pro-apoptotic oncogene activation. Thus, there is a strong selectiveadvantage for inactivation of the p53 pathway in tumors, and it has beenproposed that eliminating p53 function may be a prerequisite for tumorsurvival. Absence of p53 function is a continuous requirement for themaintenance of established tumors. When p53 function is restored totumors with inactivated p53, the tumors regressed. p53 is inactivated bymutation and/or loss in 50% of solid tumors and 10% of liquid tumors.Other key members of the p53 pathway are also genetically orepigenetically altered in cancer.

Mutations in p53 are associated with 50% of all reported human cancers(Soussi et al., 2006). Structural instability of p53 mutants leads topartial unfolding (Bullock and Fersht, 2001) which in turn may cause p53to form aggregates similar to those seen in amyloid diseases (Xu et al,2011; Levy et al, Eisenberg and Jucker, 2012). The process of p53misfolding and aggregation results in protein inactivation, therebyremoving the ‘guardian of the genome’ from its protective function (Xuet al, 2011).

There is a need for agents that can specifically destabilize p53aggregates or prevent them from forming, for use in treating forms ofcancer in which p53 is inactivated due to the fact that it is aberrantlyfolded and/or aggregated. The potential for applicability of such atargeted therapeutic agent is great.

SUMMARY

The present invention provides peptides that exhibit activity ininhibiting cell proliferation. This application relates, e.g., topeptides which bind to p53 protein molecules having an aberrant (e.g.pathological) conformation and which restore the conformation of the p53molecules having the aberrant conformation. The aberrant conformationcan be, for example, misfolding of the molecule resulting from amutation in the molecule or other factors, or the formation of amyloidaggregates of wild type or mutant p53 molecules. As a result of thetreatment with the peptides of the present invention, biological orbiochemical activities which were lost or inhibited as a result of theaberrant conformation are reactivated or restored. For example, thepeptides can inhibit further aggregation of p53 amyloid aggregatesand/or restore p53 functions such as induction or initiation ofapoptosis, inhibition of cell proliferation, and/or inducing shrinkageof a tumor.

The present invention provides highly potent peptides and modifiedpeptide agents that can efficiently reactivate p53 conformationalmutants, ideally by changing the mutant p53 proteins conformation and/oractivity to resemble that of a wild type, functional p53 protein. Thepresent invention thus provides peptides, compositions that comprise thepeptides, and their use in treating mutant p53 related conditions, whereactivation of conformationally defective p53 proteins may be beneficial.

The present invention is based on the identification of highly potentpeptide and peptide-based agents that can efficiently reactivate p53conformational mutants, more efficiently than previously known peptidesidentified for this use. The present invention thus provides, in anaspect, a recombinant or synthetic peptide comprising or consisting ofthe amino-acid sequence set forth in any one of SEQ ID NOs: 1-213,230-236 and 239.

One aspect of the invention is a peptide represented by Formulas I-III.In some variations, the peptides are capable of modulating, especiallyinhibiting, protein aggregation, including aggregation of p53 and/or p63and/or p73. Inhibitory peptides of the invention, including the activevariants, are sometimes referred to herein as “inhibitory peptides ofthe invention.”

The present disclosure moreover provides compositions, e.g.,pharmaceutical compositions, comprising any of the peptides and variantpeptides described herein and a pharmaceutically acceptable carrier, aswell as a method of treating or preventing a disease or medicalcondition (e.g., cancer) in a patient. In some variations, the methodcomprises administering to the patient a peptide or peptide variantdescribed herein, optionally formulated into a pharmaceuticalcomposition, in an amount effective to treat the disease or medicalcondition.

Other aspects of the invention include methods of inhibitingproliferation of cells, including cells with aberrant p53 and/oraberrant p63 and/or aberrant p73 expression or activity. For example,such methods comprise contacting the cells with a peptide or peptidevariant described herein. In some variations, the cells are in apatient, and the contacting comprises administering the peptide, or acomposition that comprises the peptide, to the patient. Other aspects ofthe invention will be apparent from the detailed description and claimsthat follow.

DESCRIPTION OF THE DRAWINGS

FIGS. 1(a) and 1(b) show the aggregation of p63 and p73 amyloidogenicregions, respectively. The aggregation of the p63 and p73 sequences aremonitored via Thioflavin T assay: an increase in Thioflavin Tfluorescence is detected over time due to the formation of increasingamounts of amyloid to which the dye can specifically bind.

FIGS. 2(a) and 2(b) show the in vitro inhibition of p63 and p73aggregation by several inhibitors. The aggregation is monitored viaThioflavin T assay. The inhibitors [IRIRRYR (SEQ ID NO: 12 smallcircles), TFVFRHR (SEQ ID NO: 117 small triangles), LLIKYHR (SEQ ID NO:61 large triangles), rfyyhrr (SEQ ID NO: 130 diamonds), and hqrryqr (SEQID NO: 122) large circles] are added in solution at 50 mM and delay theaggregation onset and lower the total amount of aggregates present, in aconcentration dependent fashion. The baseline of no inhibitor is theline with squares.

FIG. 3 shows electronic miscroscopy images of the formation of fibrilsfrom the aggregation of Nat1.

DETAILED DESCRIPTION

In one aspect the invention provides peptides that therapeuticallyaffect p53 related cell proliferation, more specifically cancer.

In one aspect the invention provides peptides that therapeuticallyaffect p63 related cell proliferation.

In one aspect the invention provides peptides that therapeuticallyaffect p73 related cell proliferation.

In one embodiment, the invention comprises a peptide of any of the aminoacid sequences set forth in any one of SEQ ID NO: 1-213, 230-236 and239.

In one embodiment, the invention comprises a peptide comprising an aminoacid sequence of Formula I

Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8  (I)

-   -   wherein    -   Xaa1 is Ile, Leu, Arg, Ala, Trp, Phe, Thr, Chg, Tyr, dArg, dHis,        dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe;    -   Xaa2 is Arg, homoArg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu,        Ala, Tyr, dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla,        dGln or dTrp;    -   Xaa3 is Chg, Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Phg, Ala,        Leu, dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr;    -   Xaa4 is N-Me-Lys, homoArg, Arg, Lys, Glu, Met, Gln, Ile, Leu,        Ala, Phe, Tyr, dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp,        dPhe or dTyr;    -   Xaa5 is His, Arg, Lys, Gln, Tyr, Thr, Ile, Leu, Ala, Phe, dHis,        dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr;    -   Xaa6 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, Phe,        dArg, dGln, dAla, dLys, dTyr, dTrp or dHis;    -   Xaa7 is absent, Arg, Ala, His, Thr, Ser, Glu, Lys, dArg, dLys,        dAla, dAsn, dGln, dSer, or dHis; and    -   Xaa8 is absent or Pro;    -   provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR        (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO:        221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or        IRIRAYA (SEQ ID NO: 224); further provided Xaa4 is not Ile when        Xaa7 is Glu;    -   C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide of Formula Iwherein

-   -   Xaa1 is Chg, lie, Leu, Trp, Thr or Tyr;    -   Xaa2 is homoArg, Arg, Phe, Trp, Thr, Ala or Tyr;    -   Xaa3 is Chg, Ile, Arg, Phg or Leu;    -   Xaa4 is homoArg, Arg, Lys, Ala, or Tyr;    -   Xaa5 is His, Arg, Tyr, Leu, Ala or Phe;    -   Xaa6 is Tyr, Ala, Gln, Leu, Val, His, Trp, or Phe;    -   Xaa7 is Arg, Ala, His, or Lys; and    -   Xaa8 is absent;    -   C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide of Formula Iwherein at least one amino acid is selected from

-   -   Xaa1 is Chg;    -   Xaa2 is homoArg;    -   Xaa3 is Phg or Chg; and    -   Xaa4 is homoArg;        C-terminal acids and amides and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide comprising an aminoacid sequence of Formula Ia

(SEQ ID NO: 1) Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8 (Ia)

-   -   wherein    -   Xaa1 is Ile, Leu, Arg, Ala, Trp, Phe, Thr, Chg, Phg, Tyr, dArg,        dHis, dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe;    -   Xaa2 is Arg, homoArg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu,        Ala, Tyr, dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla,        dGln or dTrp;    -   Xaa3 is Chg, lie, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Phg, Ala,        Leu, dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr;    -   Xaa4 is N-Me-Lys, homoArg, Arg, Lys, Glu, Met, Gln, lie, Leu,        Ala, Phe, Tyr, dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp,        dPhe or dTyr;    -   Xaa5 is His, Arg, Lys, Gln, Tyr, Thr, lie, Leu, Ala, Phe, dHis,        dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr;    -   Xaa6 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, Phe,        dArg, dGln, dAla, dLys, dTyr, dTrp or dHis;    -   Xaa7 is absent, Arg, Ala, His, Thr, Ser, Glu, Lys, dArg, dLys,        dAla, dAsn, dGln, dSer, or dHis; and    -   Xaa8 is absent or Pro;    -   provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR        (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO:        221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or        IRIRAYA (SEQ ID NO: 224); further provided Xaa4 is not Ile when        Xaa7 is Glu;    -   C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide of Formula Iawherein

-   -   Xaa1 is Chg, Phg, lie, Leu, Trp, Thr or Tyr;    -   Xaa2 is homoArg, Arg, Phe, Trp, Thr, Ala or Tyr;    -   Xaa3 is Chg, lie, Arg, Phg or Leu;    -   Xaa4 is homoArg, Arg, Lys, Ala, or Tyr;    -   Xaa5 is His, Arg, Tyr, Leu, Ala or Phe;    -   Xaa6 is Tyr, Ala, Gln, Leu, Val, His, Trp, or Phe;    -   Xaa7 is Arg, Ala, His, or Lys; and    -   Xaa8 is absent;    -   C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide of Formula Iawherein at least one amino acid is selected from

-   -   Xaa1 is Chg or Phg;    -   Xaa2 is homoArg;    -   Xaa3 is Phg or Chg; and    -   Xaa4 is homoArg;        C-terminal acids and amides and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide selected from

(SEQ ID NO: 2) Ile-Arg-Phg-Arg-Arg-Tyr-Arg, (SEQ ID NO: 3)Ile-homoArg-Ile-homoArg-Arg-Tyr-Arg, (SEQ ID NO: 4)Phg-Arg-Phg-Arg-Arg-Tyr-Arg, (SEQ ID NO: 5)Ile-Arg-Ile-homoArg-Arg-Tyr-Arg, (SEQ ID NO: 6)Ile-homoArg-Ile-homoArg-Arg-Trp-Arg, (SEQ ID NO: 7)Chg-Arg-Chg-Arg-Arg-Tyr-Arg, and (SEQ ID NO: 8)Ile-Arg-Chg-Arg-Arg-Tyr-Arg,

-   -   C-terminal acids and amides and N-acetyl derivatives thereof;        and a pharmaceutically acceptable salt thereof.

In one embodiment, the invention comprises a peptide comprising an aminoacid sequence of Formula II

Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30  (II)

wherein

-   -   Xaa23 is Ile, Leu, Arg, Ala, Trp, Phe, Thr or Tyr;    -   Xaa24 is Arg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu, Ala or        Tyr;    -   Xaa25 is Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Ala, or Leu;    -   Xaa26 is Arg, Lys, N-Me-Lys, Glu, Met, Gln, Ile, Leu, Ala, Phe,        or Tyr;    -   Xaa27 is His, Arg, Lys, Gln, Tyr, Thr, Ile, Leu, Ala or Phe;    -   Xaa28 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, or        Phe;    -   Xaa29 is absent, Arg, Pro, Arg, Ala, His, Thr, Ser, Glu or Lys;        and    -   Xaa30 is Pro or absent;        provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR        (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO:        221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or        IRIRAYA (SEQ ID NO: 224); further provided Xaa26 is not Ile when        Xaa29 is Glu;        C-terminal acids and amides and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide comprising an aminoacid sequence of Formula IIa

(SEQ ID NO: 9) Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30 (IIa)wherein

-   -   Xaa23 is Ile, Leu, Arg, Ala, Trp, Phe, Thr or Tyr;    -   Xaa24 is Arg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu, Ala or        Tyr;    -   Xaa25 is Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Ala, or Leu;    -   Xaa26 is Arg, Lys, N-Me-Lys, Glu, Met, Gln, Ile, Leu, Ala, Phe,        or Tyr;    -   Xaa27 is His, Arg, Lys, Gln, Tyr, Thr, Ile, Leu, Ala or Phe;    -   Xaa28 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, or        Phe;    -   Xaa29 is absent, Arg, Ala, His, Thr, Ser, Glu or Lys; and    -   Xaa30 is Pro or absent;        provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR        (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO:        221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or        IRIRAYA (SEQ ID NO: 224); further provided Xaa26 is not Ile when        Xaa29 is Glu;        C-terminal acids and amides and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide of Formula IIwherein

-   -   Xaa23 is Ile, Leu, Trp, Thr or Tyr;    -   Xaa24 is Arg, Phe, Trp, Thr, Ala or Tyr;    -   Xaa25 is Ile, Arg, or Leu;    -   Xaa26 is Arg, Lys, Ala, or Tyr;    -   Xaa27 is His, Arg, Tyr, Leu, Ala or Phe;    -   Xaa28 is Tyr, Ala, Gln, Leu, Val, His, Trp, or Phe;    -   Xaa29 is Arg, Ala, His, or Lys; and    -   Xaa30 is absent;        C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention comprises a peptide selected from

(SEQ ID NO: 10) LTRITYH, (SEQ ID NO: 11) IRIRHYR, (SEQ ID NO: 12)IRIRRYR, (SEQ ID NO: 13) IRIRAYR, (SEQ ID NO: 14) LRIRYWK,(SEQ ID NO: 15) IRIRRAR, (SEQ ID NO: 16) IRIARYR, (SEQ ID NO: 17)IRIRRYA, (SEQ ID NO: 18) IRIYRYK, (SEQ ID NO: 19) TRIRFYR,(SEQ ID NO: 20) Ac-IRIRRYR-NH2, (SEQ ID NO: 21) LYIRYLR, (SEQ ID NO: 22)LRIKYHR, (SEQ ID NO: 23) IAIRRYR, (SEQ ID NO: 24) LRIRRYR,(SEQ ID NO: 25) LWIKYHR, (SEQ ID NO: 26) IRIRRWR, (SEQ ID NO: 27)LRIYRVR, (SEQ ID NO: 28) WTIKLWH, (SEQ ID NO: 29) LRIRFFR,(SEQ ID NO: 30) LTIRYYK, (SEQ ID NO: 31) YRLRYLR, (SEQ ID NO: 32)LFRYYQK, (SEQ ID NO: 33) LVIRYHR, (SEQ ID NO: 34) RFYRYLR,(SEQ ID NO: 35) LRI(N-Me)KYHR, (SEQ ID NO: 36) IRIRHYRP, (SEQ ID NO: 37)ARIRRYR, (SEQ ID NO: 38) LRLRHYR, (SEQ ID NO: 39) LYIKYHR,(SEQ ID NO: 40) YTRITYH, (SEQ ID NO: 41) LRIYHHK, (SEQ ID NO: 42)IRLRRYR, (SEQ ID NO: 43) YRLRYVR, (SEQ ID NO: 44) LYIRYTH,(SEQ ID NO: 45) LRIRHYT, (SEQ ID NO: 46) FRIRRYR, (SEQ ID NO: 47)LYIRLTH, (SEQ ID NO: 48) LTIRLWH, (SEQ ID NO: 49) LYIRTLH,(SEQ ID NO: 50) WTIRYYK, (SEQ ID NO: 51) IRIRRY, (SEQ ID NO: 52)LFIKYHR, (SEQ ID NO: 53) TRIYRYK, (SEQ ID NO: 54) WTIRYYH,(SEQ ID NO: 55) LAIKYHR, (SEQ ID NO: 56) WTRITLK, (SEQ ID NO: 57)LTIKLWH, (SEQ ID NO: 58) LLIKYHA, (SEQ ID NO: 59) WTRIYLH,(SEQ ID NO: 60) LRIRHVK, (SEQ ID NO: 61) LLIKYHR, (SEQ ID NO: 62)IRIRRAA, (SEQ ID NO: 63) LYIRTYH, (SEQ ID NO: 64) LLIKAHR,(SEQ ID NO: 65) WYIRLWK, (SEQ ID NO: 66) IYIYHQR, (SEQ ID NO: 67)RLYIRLS, (SEQ ID NO: 68) WYIRTYH, (SEQ ID NO: 69) WYIRLWH,(SEQ ID NO: 70) LTIRTWH, (SEQ ID NO: 71) LLIKYAR, (SEQ ID NO: 72)LYIRTWH, (SEQ ID NO: 73) LYIRHK, (SEQ ID NO: 74) LTIRLTH,(SEQ ID NO: 75) LR(N-Me)IKYHR, (SEQ ID NO: 76) TLIIYHR, (SEQ ID NO: 77)LYIFRHT, (SEQ ID NO: 78) WYIRLTH, (SEQ ID NO: 79) WTRILWH,(SEQ ID NO: 80) TYIRYLR, (SEQ ID NO: 81) WTRIYYH, (SEQ ID NO: 82)LTIMLWH, (SEQ ID NO: 83) WTKITLH, (SEQ ID NO: 84) LFIYYQR,(SEQ ID NO: 85) IQIYRYK, (SEQ ID NO: 86) IRIRAAR, (SEQ ID NO: 87)LLIAYHR, (SEQ ID NO: 88) LFIFYHR, (SEQ ID NO: 89) IRVYKYS,(SEQ ID NO: 90) LTIQLWH, (SEQ ID NO: 91) YYIRYYK, (SEQ ID NO: 92)IRFRRYR, (SEQ ID NO: 93) WRIRRYR, (SEQ ID NO: 94) WTIMLWH,(SEQ ID NO: 95) LTIRTLH, (SEQ ID NO: 96) ALIKYHR, (SEQ ID NO: 97)LHIEHR, (SEQ ID NO: 98) IFVYHH, (SEQ ID NO: 99) WTIKLTH,(SEQ ID NO: 100) IHIEIK, (SEQ ID NO: 101) WTIRTWH, (SEQ ID NO: 102)YTYMLWK, (SEQ ID NO: 103) LSIRQH, (SEQ ID NO: 104) IRARRYR,(SEQ ID NO: 105) YYIRTYH, (SEQ ID NO: 106) LLAKYHR, (SEQ ID NO: 107)IWIRRWR, (SEQ ID NO: 108) AYYYRHR, (SEQ ID NO: 109) TYVYRRR,(SEQ ID NO: 110) TRIYRVK, (SEQ ID NO: 111) TYIYRQR, (SEQ ID NO: 112)LTRILTH, (SEQ ID NO: 113) ILRLYFR, (SEQ ID NO: 114) FFRLYLR,(SEQ ID NO: 115) LTRILWH, (SEQ ID NO: 116) FRLYIH, (SEQ ID NO: 117)TFVFRHR, (SEQ ID NO: 118) IRIRRYE, (SEQ ID NO: 119) YTIQLWH,(SEQ ID NO: 120) TFILRLT, and (SEQ ID NO: 121) YTYEYWH;

-   -   C-terminal acids and amides and N-acetyl derivatives thereof;        and a pharmaceutically acceptable salt thereof.

In one embodiment, the invention comprises a peptide selected from

(SEQ ID NO: 11) IRIRHYR, (SEQ ID NO: 12) IRIRRYR, (SEQ ID NO: 14)LRIRYWK, (SEQ ID NO: 18) IRIYRYK, (SEQ ID NO: 19) TRIRFYR,(SEQ ID NO: 28) WTIKLWH, (SEQ ID NO: 29) LRIRFFR, and (SEQ ID NO: 38)LRLRHYR,C-terminal acids and amides and N-acetyl derivatives thereof; and apharmaceutically acceptable salt thereof.

An embodiment of the invention comprises a peptide of the amino acidsequence IRIRHYR (SEQ ID NO: 11). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 11. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 11, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 11.

An embodiment of the invention comprises a peptide of the amino acidsequence IRIRRYR (SEQ ID NO: 12). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 12. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 12, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 12.

An embodiment of the invention comprises a peptide of the amino acidsequence LRIRYWK (SEQ ID NO: 14). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 14. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 14, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 14.

An embodiment of the invention comprises a peptide of the amino acidsequence IRIYRYK (SEQ ID NO: 18). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 18. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 18, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 18.

An embodiment of the invention comprises a peptide of the amino acidsequence TRIRFYR (SEQ ID NO: 19). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 19. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 19, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 19.

An embodiment of the invention comprises a peptide of the amino acidsequence WTIKLWH (SEQ ID NO: 28). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 28. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 28, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 28.

An embodiment of the invention comprises a peptide of the amino acidsequence LRIRFFR (SEQ ID NO: 29). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 29. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 29, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 29.

An embodiment of the invention comprises a peptide of the amino acidsequence LRLRHYR (SEQ ID NO: 38). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 38. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 38, wherein in one or more of the positions 1, 2,3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQ IDNO: 38.

An embodiment of the invention comprises a peptide comprising an aminoacid sequence of Formula III

(III) (SEQ ID NO: 201) Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15 wherein

-   -   Xaa9 is dArg, dHis, dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla,        dGln or dPhe;    -   Xaa10 is dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla,        dGln or dTrp;    -   Xaa11 is dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr;    -   Xaa12 is dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp, dPhe or        dTyr;    -   Xaa13 is dHis, dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr;    -   Xaa14 is dArg, dGln, dAla, dLys, dTyr, dTrp or dHis; and    -   Xaa15 is dArg, dLys, dAla, dAsn, dGln, dSer, dHis or absent;        C-terminal acids and amides and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

An embodiment of the invention comprises a peptide of Formula IIIwherein

-   -   Xaa9 is dArg, dHis, dLeu, dLys, dTyr, dSer, dTrp, dGln or dPhe;    -   Xaa10 is dPhe, dLeu, dIle, dTyr, dGln or dTrp;    -   Xaa11 is dArg, dLys, dHis, dGlu, dTrp or dTyr;    -   Xaa12 is dArg, dLys, dIle, dTrp, dPhe or dTyr;    -   Xaa13 is dHis, dArg, dLys, dLeu, dTrp, dPhe or dTyr;    -   Xaa14 is dArg, dGln, dTrp or dHis; and    -   Xaa15 is dArg, dLys, dAsn, dHis or absent;        C-terminal acids and amides and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

An embodiment of the invention comprises a peptide selected from

(SEQ ID NO: 122) hqrryqr, (SEQ ID NO: 123) kfrfyhr, (SEQ ID NO: 124)rihyfrr, (SEQ ID NO: 125) hwrwlrr, (SEQ ID NO: 126) rwrylrr,(SEQ ID NO: 127) rfhyfrk, (SEQ ID NO: 128) klkklh, (SEQ ID NO: 129)kwrwyrr, (SEQ ID NO: 130) rfyyhrr, (SEQ ID NO: 131) wwrwyrr,(SEQ ID NO: 132) rfyrrhr, (SEQ ID NO: 133) kyrwyrh, (SEQ ID NO: 134)fwrwhr, (SEQ ID NO: 135) qqryywr, (SEQ ID NO: 136) hlriwrn,(SEQ ID NO: 137) ffrfhrr, (SEQ ID NO: 138) lwrryhr, (SEQ ID NO: 139)rirwywk, (SEQ ID NO: 140) yqwrhwr, (SEQ ID NO: 141) rwywhhr,(SEQ ID NO: 142) sfwykrr, (SEQ ID NO: 143) rfefrhr, (SEQ ID NO: 144)yqyyyqr, (SEQ ID NO: 145) rqwyhwr, (SEQ ID NO: 146) hqryywr,(SEQ ID NO: 147) hwryhrr, (SEQ ID NO: 148) rwhwhwr, (SEQ ID NO: 149)fwrwhrr, (SEQ ID NO: 150) ffrfhhr, (SEQ ID NO: 151) rwrwhhr,(SEQ ID NO: 152) hwrwywk, (SEQ ID NO: 153) fwrhkhr, (SEQ ID NO: 154)qiryfrr, (SEQ ID NO: 155) fwrwarr, (SEQ ID NO: 156) qfrmhhr,(SEQ ID NO: 157) yqyyfwr, (SEQ ID NO: 158) swwfrhr, (SEQ ID NO: 159)yqwryrr, (SEQ ID NO: 160) hlryhrk, (SEQ ID NO: 161) yqwyrwq,(SEQ ID NO: 162) lwrwyrr, (SEQ ID NO: 163) rwrilqk, (SEQ ID NO: 164)rqhyrwr, (SEQ ID NO: 165) rlhwkhh, (SEQ ID NO: 166) rwmywqr,(SEQ ID NO: 167) fwrwhra, (SEQ ID NO: 168) rqmqyrr, (SEQ ID NO: 169)fwawhrr, (SEQ ID NO: 170) rfyrhhr, (SEQ ID NO: 171) fwrwhar,(SEQ ID NO: 172) hwrwrwr, (SEQ ID NO: 173) krwrhqr, (SEQ ID NO: 174)wwrrhhr, (SEQ ID NO: 175) kqwyhwr, (SEQ ID NO: 176) awrwhrr,(SEQ ID NO: 177) farwhrr, (SEQ ID NO: 178) fwrahrr, (SEQ ID NO: 179)rqhyhwr, (SEQ ID NO: 180) swrwhhr, (SEQ ID NO: 181) shwrrhr,(SEQ ID NO: 182) ywqwrqs, (SEQ ID NO: 183) yqwqyqr, (SEQ ID NO: 184)fwrwhaa, (SEQ ID NO: 185) wwrfhwr, (SEQ ID NO: 186) rllcwrw,(SEQ ID NO: 187) qlkwlh, (SEQ ID NO: 188) farahrr, (SEQ ID NO: 189)klkwlw, (SEQ ID NO: 190) ilkwlw, (SEQ ID NO: 191) shwrhhr,(SEQ ID NO: 192) rqwyrwq, (SEQ ID NO: 193) qwrwrhr, (SEQ ID NO: 194)qvryhkn, (SEQ ID NO: 195) klkwqw, (SEQ ID NO: 196) klkway,(SEQ ID NO: 197) rmwrhhr, (SEQ ID NO: 198) qfhykrr, (SEQ ID NO: 199)rfhrhhr, and (SEQ ID NO: 200) hqrqyqr;C-terminal acids and amides and N-acetyl derivatives thereof; and apharmaceutically acceptable salt thereof.

An embodiment of the invention comprises a peptide of Formula IIIselected from

(SEQ ID NO: 130) rfyyhrr, (SEQ ID NO: 138) lwrryhr, (SEQ ID NO: 135)qqryywr (SEQ ID NO: 161) yqwyrwq (SEQ ID NO: 124) rihyfrr,(SEQ ID NO: 129) kwrwyrr, (SEQ ID NO: 136) hlriwrn, (SEQ ID NO: 200)hqrqyqr (SEQ ID NO: 123) kfrfyhr, or (SEQ ID NO: 150) ffrfhhr;

-   -   C-terminal acids and amides and N-acetyl derivatives thereof; or        a pharmaceutically acceptable salt thereof.

An embodiment of the invention comprises a peptide of the amino acidsequence rfyyhrr (SEQ ID NO: 130). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 130. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 130, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 130.

An embodiment of the invention comprises a peptide of the amino acidsequence lwrryhr (SEQ ID NO: 138). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 138. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 138, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 138.

An embodiment of the invention comprises a peptide of the amino acidsequence kfrfyhr (SEQ ID NO: 123). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 123. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 123, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 123.

An embodiment of the invention comprises a peptide of the amino acidsequence ffrfhhr (SEQ ID NO: 150). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 150. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 150, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 150.

An embodiment of the invention comprises a peptide of the amino acidsequence qqryywr (SEQ ID NO: 135). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 135. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 135, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 135.

An embodiment of the invention comprises a peptide of the amino acidsequence yqwyrwq (SEQ ID NO: 161). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 161. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 161, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 161.

An embodiment of the invention comprises a peptide of the amino acidsequence rihyfrr (SEQ ID NO: 124). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 124. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 124, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 124.

An embodiment of the invention comprises a peptide of the amino acidsequence kwrwyrr (SEQ ID NO: 129). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 129. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 129, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 129.

An embodiment of the invention comprises a peptide of the amino acidsequence hlriwrn (SEQ ID NO: 136). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 136. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 136, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 136.

An embodiment of the invention comprises a peptide of the amino acidsequence hqrqyqr (SEQ ID NO: 200). In some embodiments a peptideaccording to the present invention comprises up to 2 amino acidmodifications relative to SEQ ID NO: 200. In some embodiments a peptideaccording to the present invention comprises 1 amino acid modificationrelative to SEQ ID NO: 200, wherein in one or more of the positions 1,2, 3, 4, 5, 6 or 7, wherein the amino acid numbering corresponds to SEQID NO: 200.

In some embodiments a peptide according to the invention is representedby the compounds listed in Table 1.

TABLE 1 Sequence SEQ ID NO: Ile-Arg-Phg-Arg-Arg-Tyr-Arg (SEQ ID NO: 2),Ile-homoArg-Ile-homoArg-Arg- (SEQ ID NO: 3), Tyr-ArgPhg-Arg-Phg-Arg-Arg-Tyr-Arg (SEQ ID NO: 4), Ile-Arg-Ile-homoArg-Arg-Tyr-(SEQ ID NO: 5), Arg Ile-homoArg-Ile-homoArg-Arg- (SEQ ID NO: 6), Trp-ArgChg-Arg-Chg-Arg-Arg-Tyr-Arg (SEQ ID NO: 7), Ile-Arg-Chg-Arg-Arg-Tyr-Arg(SEQ ID NO: 8), LTRITYH (SEQ ID NO: 10), IRIRHYR (SEQ ID NO: 11),IRIRRYR (SEQ ID NO: 12), IRIRAYR (SEQ ID NO: 13), LRIRYWK(SEQ ID NO: 14), IRIRRAR (SEQ ID NO: 15), IRIARYR (SEQ ID NO: 16),IRIRRYA (SEQ ID NO: 17), IRIYRYK (SEQ ID NO: 18), TRIRFYR(SEQ ID NO: 19), Ac-IRIRRYR-NH2 (SEQ ID NO: 20), LYIRYLR(SEQ ID NO: 21), LRIKYHR (SEQ ID NO: 22), IAIRRYR (SEQ ID NO: 23),LRIRRYR (SEQ ID NO: 24), LWIKYHR (SEQ ID NO: 25), IRIRRWR(SEQ ID NO: 26), LRIYRVR (SEQ ID NO: 27), WTIKLWH (SEQ ID NO: 28),LRIRFFR (SEQ ID NO: 29), LTIRYYK (SEQ ID NO: 30), YRLRYLR(SEQ ID NO: 31), LFRYYQK (SEQ ID NO: 32), LVIRYHR (SEQ ID NO: 33),RFYRYLR (SEQ ID NO: 34), LRI(N-Me)KYHR (SEQ ID NO: 35), IRIRHYRP(SEQ ID NO: 36), ARIRRYR (SEQ ID NO: 37), LRLRHYR (SEQ ID NO: 38),LYIKYHR (SEQ ID NO: 39), YTRITYH (SEQ ID NO: 40), LRIYHHK(SEQ ID NO: 41), IRLRRYR (SEQ ID NO: 42), YRLRYVR (SEQ ID NO: 43),LYIRYTH (SEQ ID NO: 44), LRIRHYT (SEQ ID NO: 45), FRIRRYR(SEQ ID NO: 46), LYIRLTH (SEQ ID NO: 47), LTIRLWH (SEQ ID NO: 48),LYIRTLH (SEQ ID NO: 49), WTIRYYK (SEQ ID NO: 50), IRIRRY(SEQ ID NO: 51), LFIKYHR (SEQ ID NO: 52), TRIYRYK (SEQ ID NO: 53),WTIRYYH (SEQ ID NO: 54), LAIKYHR (SEQ ID NO: 55), WTRITLK(SEQ ID NO: 56), LTIKLWH (SEQ ID NO: 57), LLIKYHA (SEQ ID NO: 58),WTRIYLH (SEQ ID NO: 59), LRIRHVK (SEQ ID NO: 60), LLIKYHR(SEQ ID NO: 61), IRIRRAA (SEQ ID NO: 62), LYIRTYH (SEQ ID NO: 63),LLIKAHR (SEQ ID NO: 64), WYIRLWK (SEQ ID NO: 65), IYIYHQR(SEQ ID NO: 66), RLYIRLS (SEQ ID NO: 67), WYIRTYH (SEQ ID NO: 68),WYIRLWH (SEQ ID NO: 69), LTIRTWH (SEQ ID NO: 70), LLIKYAR(SEQ ID NO: 71), LYIRTWH (SEQ ID NO: 72), LYIRHK (SEQ ID NO: 73),LTIRLTH (SEQ ID NO: 74), LR(N-Me)IKYHR (SEQ ID NO: 75), TLIIYHR(SEQ ID NO: 76), LYIFRHT (SEQ ID NO: 77), WYIRLTH (SEQ ID NO: 78),WTRILWH (SEQ ID NO: 79), TYIRYLR (SEQ ID NO: 80), WTRIYYH(SEQ ID NO: 81), LTIMLWH (SEQ ID NO: 82), WTKITLH (SEQ ID NO: 83),LFIYYQR (SEQ ID NO: 84), IQIYRYK (SEQ ID NO: 85), IRIRAAR(SEQ ID NO: 86), LLIAYHR (SEQ ID NO: 87), LFIFYHR (SEQ ID NO: 88),IRVYKYS (SEQ ID NO: 89), LTIQLWH (SEQ ID NO: 90), YYIRYYK(SEQ ID NO: 91), IRFRRYR (SEQ ID NO: 92), WRIRRYR (SEQ ID NO: 93),WTIMLWH (SEQ ID NO: 94), LTIRTLH (SEQ ID NO: 95), ALIKYHR(SEQ ID NO: 96), LHIEHR (SEQ ID NO: 97), IFVYHH (SEQ ID NO: 98), WTIKLTH(SEQ ID NO: 99), IHIEIK (SEQ ID NO: 100), WTIRTWH (SEQ ID NO: 101),YTYMLWK (SEQ ID NO: 102), LSIRQH (SEQ ID NO: 103), IRARRYR(SEQ ID NO: 104), YYIRTYH (SEQ ID NO: 105), LLAKYHR (SEQ ID NO: 106),IWIRRWR (SEQ ID NO: 107), AYYYRHR (SEQ ID NO: 108), TYVYRRR(SEQ ID NO: 109), TRIYRVK (SEQ ID NO: 110), TYIYRQR (SEQ ID NO: 111),LTRILTH (SEQ ID NO: 112), ILRLYFR (SEQ ID NO: 113), FFRLYLR(SEQ ID NO: 114), LTRILWH (SEQ ID NO: 115), FRLYIH (SEQ ID NO: 116),TFVFRHR (SEQ ID NO: 117), IRIRRYE (SEQ ID NO: 118), YTIQLWH(SEQ ID NO: 119), TFILRLT (SEQ ID NO: 120), YTYEYWH (SEQ ID NO: 121),hqrryqr (SEQ ID NO: 122) kfrfyhr (SEQ ID NO: 123), rihyfrr(SEQ ID NO: 124), hwrwlrr (SEQ ID NO: 125), rwrylrr (SEQ ID NO: 126),rfhyfrk (SEQ ID NO: 127), klkklh (SEQ ID NO: 128), kwrwyrr(SEQ ID NO: 129), rfyyhrr (SEQ ID NO: 130), wwrwyrr (SEQ ID NO: 131),rfyrrhr (SEQ ID NO: 132), kyrwyrh (SEQ ID NO: 133), fwrwhr(SEQ ID NO: 134), qqryywr (SEQ ID NO: 135), hlriwrn (SEQ ID NO: 136),ffrfhrr (SEQ ID NO: 137), lwrryhr (SEQ ID NO: 138), rirwywk(SEQ ID NO: 139), yqwrhwr (SEQ ID NO: 140), rwywhhr (SEQ ID NO: 141),sfwykrr (SEQ ID NO: 142), rfefrhr (SEQ ID NO: 143), yqyyyqr(SEQ ID NO: 144), rqwyhwr (SEQ ID NO: 145), hqryywr (SEQ ID NO: 146),hwryhrr (SEQ ID NO: 147), rwhwhwr (SEQ ID NO: 148), fwrwhrr(SEQ ID NO: 149), ffrfhhr (SEQ ID NO: 150), rwrwhhr (SEQ ID NO: 151),hwrwywk (SEQ ID NO: 152), fwrhkhr (SEQ ID NO: 153), qiryfrr(SEQ ID NO: 154), fwrwarr (SEQ ID NO: 155), qfrmhhr (SEQ ID NO: 156),yqyyfwr (SEQ ID NO: 157), swwfrhr (SEQ ID NO: 158), yqwryrr(SEQ ID NO: 159), hlryhrk (SEQ ID NO: 160), yqwyrwq (SEQ ID NO: 161),lwrwyrr (SEQ ID NO: 162), rwrilqk (SEQ ID NO: 163), rqhyrwr(SEQ ID NO: 164), rlhwkhh (SEQ ID NO: 165), rwmywqr (SEQ ID NO: 166),fwrwhra (SEQ ID NO: 167), rqmqyrr (SEQ ID NO: 168), fwawhrr(SEQ ID NO: 169), rfyrhhr (SEQ ID NO: 170), fwrwhar (SEQ ID NO: 171),hwrwrwr (SEQ ID NO: 172), krwrhqr (SEQ ID NO: 173), wwrrhhr(SEQ ID NO: 174), kqwyhwr (SEQ ID NO: 175), awrwhrr (SEQ ID NO: 176),farwhrr (SEQ ID NO: 177), fwrahrr (SEQ ID NO: 178), rqhyhwr(SEQ ID NO: 179), swrwhhr (SEQ ID NO: 180), shwrrhr (SEQ ID NO: 181),ywqwrqs (SEQ ID NO: 182), yqwqyqr (SEQ ID NO: 183), fwrwhaa(SEQ ID NO: 184), wwrfhwr (SEQ ID NO: 185), rllcwrw (SEQ ID NO: 186),qlkwlh (SEQ ID NO: 187), farahrr (SEQ ID NO: 188), klkwlw(SEQ ID NO: 189), ilkwlw (SEQ ID NO: 190), shwrhhr (SEQ ID NO: 191),rqwyrwq (SEQ ID NO: 192), qwrwrhr (SEQ ID NO: 193), qvryhkn(SEQ ID NO: 194), klkwqw (SEQ ID NO: 195), klkway (SEQ ID NO: 196),rmwrhhr (SEQ ID NO: 197), qfhykrr (SEQ ID NO: 198), rfhrhhr(SEQ ID NO: 199), and hqrqyqr (SEQ ID NO: 200).

An embodiment of the invention comprises a peptide comprising an aminoacid sequence of Formula I′ or II″:

(I′) (SEQ ID NO: 202)(Arg)_(n)-Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7- Xaa8 (I″)(SEQ ID NO: 239) (dArg)_(n)-Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8wherein

-   -   n is a number between 1 and 16, inclusive;    -   Xaa1 is Ile, Leu, Arg, Ala, Trp, Phe, Thr, Chg, Tyr, dArg, dHis,        dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe;    -   Xaa2 is Arg, homoArg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu,        Ala, Tyr, dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla,        dGln or dTrp;    -   Xaa3 is Chg, Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Phg, Ala,        Leu, dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr;    -   Xaa4 is N-Me-Lys, homoArg, Arg, Lys, Glu, Met, Gln, Ile, Leu,        Ala, Phe, Tyr, dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp,        dPhe or dTyr;    -   Xaa5 is His, Arg, Lys, Gln, Tyr, Thr, Ile, Leu, Ala, Phe, dHis,        dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr;    -   Xaa6 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, Phe,        dArg, dGln, dAla, dLys, dTyr, dTrp or dHis;    -   Xaa7 is absent, Arg, Ala, His, Thr, Ser, Glu, Lys, dArg, dLys,        dAla, dAsn, dGln, dSer, or dHis; and    -   Xaa8 is absent or Pro;        provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR        (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO:        221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or        IRIRAYA (SEQ ID NO: 224; further provided Xaa4 is not Ile when        Xaa7 is Glu;        C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

An embodiment of the invention comprises a peptide comprising an aminoacid sequence of Formula Ia′ or Ia″:

(Ia′) (SEQ ID NO: 202)(Arg)_(n)-Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7- Xaa8 (Ia″)(SEQ ID NO: 239) (dArg)_(n)-Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8wherein

-   -   n is a number between 1 and 16, inclusive;    -   Xaa1 is Ile, Leu, Arg, Ala, Trp, Phe, Thr, Chg, Phg, Tyr, dArg,        dHis, dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe;    -   Xaa2 is Arg, homoArg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu,        Ala, Tyr, dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla,        dGln or dTrp;    -   Xaa3 is Chg, Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Phg, Ala,        Leu, dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr;    -   Xaa4 is N-Me-Lys, homoArg, Arg, Lys, Glu, Met, Gln, Ile, Leu,        Ala, Phe, Tyr, dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp,        dPhe or dTyr;    -   Xaa5 is His, Arg, Lys, Gln, Tyr, Thr, Ile, Leu, Ala, Phe, dHis,        dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr;    -   Xaa6 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, Phe,        dArg, dGln, dAla, dLys, dTyr, dTrp or dHis;    -   Xaa7 is absent, Arg, Ala, His, Thr, Ser, Glu, Lys, dArg, dLys,        dAla, dAsn, dGln, dSer, or dHis; and    -   Xaa8 is absent or Pro;        provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR        (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO:        221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or        IRIRAYA (SEQ ID NO: 224; further provided Xaa4 is not Ile when        Xaa7 is Glu;        C-terminal acids and amides, and N-acetyl derivatives thereof;        and pharmaceutically acceptable salts thereof.

An embodiment of the invention comprises a CPP of a peptide of Formula Iselected from RRRRRRRRRRPIIRIRHYR (SEQ ID NO: 203); RRRRRRRRRRPIIRIRHYP(SEQ ID NO: 204); PRRRRRRRRRRPIIRIRHYRP (SEQ ID NO: 205);RRRRRRRRRRPIIRIRHYRP (SEQ ID NO: 206); PRRRRRRRRRRPILRIRYWKP (SEQ ID NO:207); PRRRRRRRRRRPITRIRFYRP (SEQ ID NO: 208); PRRRRRRRRRRPIWTIKLWHP (SEQID NO: 209); RRRRRRRRRRPIqqryywr (SEQ ID NO: 210); RRRRRRRRRRPIyqwyrwq(SEQ ID NO: 211); RRRRRRRRRRPIkfrfyhr (SEQ ID NO: 212); andRRRRRRRRRRPIrfyyhrr (SEQ ID NO: 213); or a pharmaceutically acceptablesalt thereof.

In some embodiments, the present invention also relates to a peptidecomprising a sequence having at least 66% sequence identity to any oneof amino acid sequences SEQ ID NO: 1-213, 230-236 and 239. In certainembodiments, the % identity is selected from, e.g., at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, or at least 95%, ormore sequence identity to a given sequence. In certain embodiments, the% identity is in the range of, e.g., about 65% to about 70%, about 70%to about 80%, about 80% to about 85%, about 85% to about 90%, or about90% to about 95%.

Peptides of the disclosure include peptides that have been modified inany way and for any reason, for example, to: (1) reduce susceptibilityto proteolysis, (2) alter binding affinities, and (3) confer or modifyother physicochemical or functional properties. For example, single ormultiple amino acid substitutions (e.g., equivalent, conservative ornon-conservative substitutions, deletions or additions) may be made in asequence.

A conservative amino acid substitution refers to the substitution in apeptide of an amino acid with a functionally similar amino acid havingsimilar properties, e.g., size, charge, hydrophobicity, hydrophilicity,and/or aromaticity. The following six groups each contain amino acidsthat are conservative substitutions for one another are found in Table2.

TABLE 2 i. Alanine (A), Serine (S), and Threonine (T) ii. Aspartic acid(D) and Glutamic acid (E) iii. Asparagine (N) and Glutamine (Q) iv.Arginine (R) and Lysine (K) v. Isoleucine (I), Leucine (L), Methionine(M), and Valine (V) vi. Phenylalanine (F), Tyrosine (Y), and Tryptophan(W)

Additionally, within the meaning of the term “equivalent amino acidsubstitution” as applied herein, one amino acid may be substituted foranother, in one embodiment, within the groups of amino acids indicatedherein below:

-   -   1. Amino acids with polar side chains (Asp, Glu, Lys, Arg, His,        Asn, Gln, Ser, Thr, Tyr, and Cys,)    -   2. Amino acids with small nonpolar or slightly polar residues        (Ala, Ser, Thr, Pro, Gly);    -   3. Amino acids with non-polar side chains (Gly, Ala, Val, Leu,        Ile, Phe, Trp, Pro, and Met)    -   4. Amino acids with large, aliphatic, nonpolar residues (Met,        Leu, Ile, Val, Cys, Norleucine (Nle), homocysteine)    -   5. Amino acids with aliphatic side chains (Gly, Ala Val, Leu,        Ile)    -   6. Amino acids with cyclic side chains (Phe, Tyr, Trp, His, Pro)    -   7. Amino acids with aromatic side chains (Phe, Tyr, Trp)    -   8. Amino acids with acidic side chains (Asp, Glu)    -   9. Amino acids with basic side chains (Lys, Arg, His)    -   10. Amino acids with amide side chains (Asn, Gln)    -   11. Amino acids with hydroxy side chains (Ser, Thr)    -   12. Amino acids with sulphur-containing side chains (Cys, Met),    -   13. Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser,        Thr)    -   14. Hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and    -   15. Hydrophobic amino acids (Leu, Ile, Val).

In some embodiments, the amino acid substitution is not a conservativeamino acid substitution, e.g., is a non-conservative amino acidsubstitution. This class generally includes corresponding D-amino acids,homo-amino acids, N-alkyl amino acids, beta amino acids and otherunnatural amino acids. The non-conservative amino acid substitutionsstill fall within the descriptions identified for the equivalent aminoacid substitutions above [e.g. polar, nonpolar, etc.]. Examples ofnon-conservative amino acids are provided below.

Non limiting examples for alanine non-conservative amino acids are:D-alanine [Dala, (dA), a], N-Acetyl-3-(3,4-dimethoxyphenyl)-D-alanine,N-Me-D-Ala-OH, N-Me-Ala-OH, H-β-Ala-β-naphthalene,L-(−)-2-Amino-3-ureidopropionic acid, (R)-(+)-α-Allylalanine,(S)-(−)-α-Allylalanine, D-2-Aminobutyric acid, L-2-Aminobutyric acid,DL-2-Aminobutyric acid, 2-Aminoisobutyric acid, α-Aminoisobutyric acid,(S)-(+)-2-Amino-4-phenylbutyric acid ethyl ester, Benzylα-aminoisobutyrate, Abu-OH, Aib-OH, β-(9-anthryl)-Ala-OH,β-(3-benzothienyl)-Ala-OH, β-(3-benzothienyl)-D-Ala-OH, Cha-OH, Cha-OMe,β-(2-furyl)-Ala-OH, β-(2-furyl)-D-Ala-OH, β-iodo-Ala-OBzl,β-iodo-D-Ala-OBzl, 3-iodo-D-Ala-OMe, β-iodo-Ala-OMe, 1-Nal-OH,D-1-Nal-OH, 2-Nal-OH, D-2-Nal-OH, (R)-3-(2-naphthyl)-β-Ala-OH,(S)-3-(2-naphthyl)-β-Ala-OH, β-phenyl-Phe-OH, 3-(2-pyridyl)-Ala-OH,3-(3-pyridyl)-Ala-OH, 3-(3-pyridyl)-D-Ala-OH,(S)-3-(3-pyridyl)-β-Ala-OH, 3-(4-pyridyl)-Ala-OH,3-(4-pyridyl)-D-Ala-OH, β-(2-quinolyl)-Ala-OH, 3-(2-quinolyl)-DL-Ala-OH,3-(3-quinolyl)-DL-Ala-OH, 3-(2-quinoxalyl)-DL-Ala-OH,β-(4-thiazolyl)-Ala-OH, β-(2-thienyl)-Ala-OH, β-(2-thienyl)-D-Ala-OH,β-(3-thienyl)-Ala-OH, β-(3-thienyl)-D-Ala-OH, 3-Chloro-D-alanine methylester, N-[(4-Chlorophenyl)sulfonyl]-β-alanine, 3-Cyclohexyl-D-alanine,3-Cyclopentyl-DL-alanine,(−)-3-(3,4-Dihydroxyphenyl)-2-methyl-L-alanine, 3,3-Diphenyl-D-alanine,3,3-Diphenyl-L-alanine,N—[(S)-(+)-1-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanine,N-[1-(S)-(+)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl carboxyanhydride,N-(3-fluorobenzyl)alanine, N-(3-Indolylacetyl)-L-alanine, Methyl(RS)-2-(aminomethyl)-3-phenylpropionate,3-(2-Oxo-1,2-dihydro-4-quinolinyl)alanine, 3-(1-Pyrazolyl)-L-alanine,3-(2-Pyridyl)-D-alanine, 3-(2-Pyridyl)-L-alanine,3-(3-Pyridyl)-L-alanine, 3-(4-Pyridyl)-D-alanine,3-(4-Pyridyl)-L-alanine, 3-(2-Quinolyl)-DL-alanine,3-(4-Quinolyl)-DL-alanine, D-styrylalanine, L-styrylalanine,3-(2-Thienyl)-L-alanine, 3-(2-Thienyl)-DL-alanine,3-(2-Thienyl)-DL-alanine, 3,3,3-Trifluoro-DL-alanine,N-Methyl-L-alanine, 3-Ureidopropionic acid, Aib-OH, Cha-OH,Dehydro-Ala-OMe, dehydro-Ala-OH, D-2-Nal-OH, β-Ala-ONp, β-Homoala-OH,β-D-Homoala-OH, β-Alanine, β-Alanine ethyl ester, β-Alanine methylester, (S)-diphenyl-β-Homoala-OH, (R)-4-(4-pyridyl)-β-Homoala-OH,(S)-4-(4-pyridyl)-β-Homoala-OH, β-Ala-OH, (S)-diphenyl-β-Homoala-OH,L-β-Homoalanine, (R)-4-(3-pyridyl)-β-Homoala-OH,α-methyl-α-naphthylalanine [Manap], N-methyl-cyclohexylalanine[Nmchexa], cyclohexylalanine [Chexa], N-methyl-cyclopentylalanine[Nmcpen], cyclopentylalanine [Cpen], N-methyl-α-naphthylalanine[Nmanap], α-naphthylalanine [Anap], L-N-methylalanine [Nmala],D-N-methylalanine [Dnmala], α-methyl-cyclohexylalanine [Mchexa],α-methyl-cyclopentylalanine [Mcpen]. Each possibility represents aseparate embodiment.

Non limiting examples for arginine non-conservative amino acids are:homoarginine (hArg), N-methyl arginine (NMeArg), citruline,2-amino-3-guanidinopropionic acid, N-iminoethyl-L-ornithine,Nω-monomethyl-L-arginine, Nω-nitro-L-arginine, D-arginine,2-amino-3-ureidopropionic acid, Nω,ω-dimethyl-L-arginine,Nω-Nitro-D-arginine, L-α-methylarginine [Marg], D-α-methylarginine[Dmarg], L-N-methylarginine [Nmarg], D-N-methylarginine [Dnmarg],β-Homoarg-OH, L-Homoarginine, N-(3-guanidinopropyl)glycine [Narg], andD-arginine [Darg, (dR), r]. Each possibility represents a separateembodiment.

Non limiting examples for asparagine non-conservative amino acids are:L-α-methylasparagine [Masn], D-α-methylasparagine [Dmasn],L-N-methylasparagine [Nmasn], D-N-methylasparagine [Dnmasn],N-(carbamylmethyl)glycine [Nasn] and D-asparagine [Dasn, (dN), n]. Eachpossibility represents a separate embodiment.

Non limiting examples for aspartic acid non-conservative amino acidsare: L-α-methylaspartate [Masp], D-α-methylaspartate [Dmasp],L-N-methylaspartic acid [Nmasp], D-N-methylasparatate [Dnmasp],N-(carboxymethyl)glycine [Nasp] and D-aspartic acid [Dasp, (dD), d].Each possibility represents a separate embodiment.

Non limiting examples for cysteine non-conservative amino acids are:L-Cysteic acid, L-Cysteinesulfinic acid, D-Ethionine,S-(2-Thiazolyl)-L-cysteine, DL-Homocysteine, L-Homocysteine,L-Homocystine, L-α-methylcysteine [Mcys], D-α-methylcysteine [Dmcys],L-N-methylcysteine [Nmcys], D-N-methylcysteine [Dnmcys],N-(thiomethyl)glycine [Ncys] and D-cysteine [Dcys, (dC), c]. Eachpossibility represents a separate embodiment.

Non limiting examples for glutamic acid non-conservative amino acidsare: γ-Carboxy-DL-glutamic acid, 4-Fluoro-DL-glutamic acid, β-Glutamicacid, L-β-Homoglutamic acid, L-α-methylglutamate [Mglu], D-α-methylglutamic acid [Dmglu], L-N-methylglutamic acid [Nmglu],D-N-methylglutamate [Dnmglu], N-(2-carboxyethyl)glycine [Nglu], andD-glutamic acid [Dglu, (dE), e]. Each possibility represents a separateembodiment.

Non limiting examples for glutamine non-conservative amino acids are:Cit-OH, D-Citrulline, Thio-L-citrulline, β-Gln-OH, L-β-Homoglutamine,L-α-methylglutamine [Mgln], D-α-methylglutamine [Dmgln],L-N-methylglutamine [Nmgln], D-N-methylglutamine [Dnmgln],N-(2-carbamylethyl)glycine [Ngln], and D-glutamine [Dgln, (dQ), q]. Eachpossibility represents a separate embodiment.

Non limiting examples for glycine non-conservative amino acids are:tBu-Gly-OH, D-Allylglycine, N-[Bis(methylthio)methylene]glycine methylester, Chg-OH, D-Chg-OH, D-cyclopropylglycine, L-cyclopropylglycine,(R)-4-fluorophenylglycine, (S)-4-fluorophenylglycine, iminodiaceticacid, (2-indanyl)-Gly-OH, (±)-α-phosphonoglycine trimethyl ester,D-propargylglycine, propargyl-Gly-OH, (R)-2-thienylglycine,(S)-2-thienylglycine, (R)-3-thienylglycine, (S)-3-thienylglycine,2-(4-trifluoromethyl-phenyl)-DL-glycine,(2S,3R,4S)-α-(Carboxycyclopropyl)glycine, N-(Chloroacetyl)glycine ethylester, (S)-(+)-2-chlorophenylglycine methyl ester,N-(2-chlorophenyl)-N-(methylsulfonyl)glycine, D-α-Cyclohexylglycine,L-α-Cyclopropylglycine, Di-tert-butyl-iminodicarboxylate, Ethylacetamidocyanoacetate, N-(2-fluorophenyl)-N-(methylsulfonyl) glycine,N-(4-fluorophenyl)-N-(methylsulfonyl)glycine,N-(2-Furfurylideneacetyl)glycine methyl ester, N-(2-Furoyl)glycine,N-(2-Hydroxyethyl)iminodiacetic acid, N-(4-Hydroxyphenyl)glycine,Iminodiacetic acid, N-Lauroylsarcosine sodium salt,L-α-Neopentylglycine, N-(Phosphonomethyl)glycine, D-Propargylglycine,L-C-Propargylglycine, Sarcosine, N,N-Dimethylglycine,N,N-Dimethylglycine ethyl ester, D-Chg-OH, α-Phosphonoglycine trimethylester, N-cyclobutylglycine [Ncbut], L-α-methylethylglycine [Metg],N-cycloheptylglycine [Nchep], L-α-methyl-i-butylglycine [Mtbug],N-methylglycine [Nmgly], L-N-methyl-ethylglycine [Nmetg], L-ethylglycine[Etg], L-N-methyl-t-butylglycine [Nmtbug], L-t-butylglycine [Tbug],N-cyclohexylglycine [Nchex], N-cyclodecylglycine [Ncdec],N-cyclododecylglycine [Ncdod], N-cyclooctylglycine [Ncoct],N-cyclopropylglycine [Ncpro], N-cycloundecylglycine [Ncund],N-(2-aminoethyl)glycine [Naeg], N—(N-(2,2-diphenylethyl)diphenylethyl)glycine [Nnbhm], N-(2,2-carbamylmethyl-glycine [Nbhm],N—(N-(3,3-diphenylpropyl) diphenylpropyl)glycine [Nnbhe] andN-(3,3-carbamylmethyl-glycine [Nbhe]. Each possibility represents aseparate embodiment.

Non limiting examples for histidine non-conservative amino acids are:L-α-methylhistidine [Mhis], D-α-methylhistidine [Dmhis],L-N-methylhistidine [Nmhis], D-N-methylhistidine [Dnmhis],N-(imidazolylethyl)glycine [Nhis], and D-histidine [Dhis, (dH), h]. Eachpossibility represents a separate embodiment.

Non limiting examples for isoleucine non-conservative amino acids are:N-Methyl-L-isoleucine [Nmile], N-(3-Indolylacetyl)-L-isoleucine,allo-Ile-OH, D-allo-Isoleucine, L-β-Homoisoleucine, L-α-methylisoleucine[Mile], D-α-methylisoleucine [Dmile], D-N-methylisoleucine [Dnmile],N-(1-methylpropyl)glycine [Nile], and D-isoleucine [Dile, (dD), i]. Eachpossibility represents a separate embodiment.

Non limiting examples for leucine non-conservative amino acids are:D-leuine [Dleu, (dL), l]. Cycloleucine, DL-leucine, N-Formyl-Leu-OH,D-tert-Leucine, L-tert-Leucine, DL-tert-Leucine, L-tert-Leucine methylester, 5,5,5-Trifluoro-DL-leucine, D-β-Leu-OH, L-β-Leucine,DL-β-Leucine, L-β-Homoleucine, DL-β-Homoleucine, L-N-methyl-leucine[Nmleu], D-N-methyl-leucine [Dnmleu], L-α-methyl-leucine [Mleu],D-α-methyl-leucine [Dmleu], N-(2-methylpropyl)glycine [Nleu], D-leucine[Dleu, 1], D-Norleucine, L-Norleucine, DL-Norleucine,L-N-methylnorleucine [Nmnle] and L-norleucine [Nle]. Each possibilityrepresents a separate embodiment.

Non limiting examples for lysine non-conservative amino acids are:DL-5-Hydroxylysine, (5R)-5-Hydroxy-L-lysine, β-Lys-OH, L-β-Homolysine,L-α-methyl-lysine [Mlys], D-α-methyl-lysine [Dmlys], L-N-methyl-lysine[Nmlys], D-N-methyl-lysine [Dnmlys], N-(4-aminobutyl)glycine [Nlys], andD-lysine [Dlys, (dK), k]. Each possibility represents a separateembodiment.

Non limiting examples for methionine non-conservative amino acids are:L-β-Homomethionine, DL-β-Homomethionine, L-α-methylmethionine [Mmet],D-α-methylmethionine [Dmmet], L-N-methylmethionine [Nmmet],D-N-methylmethionine [Dnmmet], N-(2-methylthioethyl)glycine [Nmet], andD-methionine [Dmet, (dM), m]. Each possibility represents a separateembodiment.

Non limiting examples for phenylalanine non-conservative amino acidsare: N-Acetyl-2-fluoro-DL-phenylalanine,N-Acetyl-4-fluoro-DL-phenylalanine, 4-Amino-L-phenylalanine,3-[3,4-bis(trifluoromethyl)phenyl]-L-alanine, Bpa-OH, D-Bpa-OH,4-tert-butyl-Phe-OH, 4-tert-butyl-D-Phe-OH, 4-(amino)-L-phenylalanine,rac-β²-homophenylalanine, 2-methoxy-L-phenylalanine,(S)-4-methoxy-β-Phe-OH, 2-nitro-L-phenylalanine,pentafluoro-D-phenylalanine, pentafluoro-L-phenylalanine, Phe(4-Br)—OH,D-Phe(4-Br)—OH, Phe(2-CF₃)—OH, D-Phe(2-CF₃)—OH, Phe(3-CF₃)—OH,D-Phe(3-CF₃)—OH, Phe(4-CF₃)—OH, D-Phe(4-CF₃)—OH, Phe(2-Cl)—OH,D-Phe(2-Cl)—OH, Phe(2,4-Cl₂)—OH, D-Phe(2,4-Cl₂)—OH, D-Phe(3-Cl)—OH,Phe(3,4-Cl₂)—OH, Phe(4-Cl)—OH, D-Phe(4-Cl)—OH, Phe(2-CN)—OH,D-Phe(2-CN)—OH, D-Phe(3-CN)—OH, Phe(4-CN)—OH, D-Phe(4-CN)—OH,Phe(2-Me)-OH, D-Phe(2-Me)-OH, Phe(3-Me)-OH, D-Phe(3-Me)-OH,Phe(4-Me)-OH, Phe(4-NH₂)—OH, Phe(4-NO₂)—OH, Phe(2-F)—OH, D-Phe(2-F)—OH,Phe(3-F)—OH, D-Phe(3-F)—OH, Phe(3,4-F₂)—OH, D-Phe(3,4-F₂)—OH,Phe(3,5-F₂)—OH, Phe(4-F)—OH, D-Phe(4-F)—OH, Phe(4-I)—OH,D-3,4,5-trifluorophenylalanine, p-Bromo-DL-phenylalanine,4-Bromo-L-phenylalanine, β-phenyl-D-phenylalanine,4-Chloro-L-phenylalanine, DL-2,3-Difluorophenylalanine,DL-3,5-Difluorophenylalanine, 3,4-Dihydroxy-L-phenylalanine,3-(3,4-Dimethoxyphenyl)-L-alanine,N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-2-methoxy-L-phenylalanine,o-Fluoro-DL-phenylalanine, m-Fluoro-L-phenylalanine,m-Fluoro-DL-phenylalanine, p-Fluoro-L-phenylalanine,p-Fluoro-DL-phenylalanine, 4-Fluoro-D-phenylalanine,2-Fluoro-L-phenylalanine methyl ester, p-fluoro-DL-Phe-OMe,D-3-bromophenylalanine, D-4-bromophenylalanine,L-β-(6-chloro-4-pyridinyl)alanine, D-3,5-difluorophenylalanine,L-3-fluorophenylalanine, L-4-fluorophenylalanine,L-β-(1H-5-indolyl)alanine, 2-nitro-L-phenylalanine,pentafluoro-L-phenylalanine, phe(3-br)-oh, Phe(4-Br)—OH, Phe(2-CF₃)—OH,D-Phe(2-CF₃)—OH, Phe(3-CF₃)—OH, D-Phe(3-CF₃)—OH, Phe(4-CF₃)—OH,D-Phe(4-CF₃)—OH, Phe(2-Cl)—OH, D-Phe(2-Cl)—OH, Phe(2,4-Cl₂)—OH,D-Phe(2,4-Cl₂)—OH, Phe(3,4-Cl₂)—OH, D-Phe(3,4-Cl₂)—OH, Phe(4-Cl)—OH,D-Phe(4-Cl)—OH, Phe(2-CN)—OH, D-Phe(2-CN)—OH, D-Phe(3-CN)—OH,Phe(4-CN)—OH, Phe(2-Me)-OH, Phe(3-Me)-OH, D-Phe(3-Me)-OH, Phe(4-NO₂)—OH,D-Phe(4-NO₂)—OH, D-Phe(2-F)—OH, Phe(3-F)—OH, D-Phe(3-F)—OH,Phe(3,4-F₂)—OH, Phe(3,5-F₂)—OH, D-Phe(4-F)—OH, Phe(4-I)—OH,D-Phe(4-I)—OH, 4-(phosphonomethyl)-Phe-OH,L-trifluoromethylphenylalanine, 3,4,5-trifluoro-D-phenylalanine,L-3,4,5-trifluorophenylalanine, 6-Hydroxy-DL-DOPA,4-(Hydroxymethyl)-D-phenylalanine, N-(3-Indolylacetyl)-L-phenylalanine,p-Iodo-D-phenylalanine, 4-Iodo-L-phenylalanine,α-Methyl-D-phenylalanine, α-Methyl-L-phenylalanine,α-Methyl-DL-phenylalanine, α-Methyl-DL-phenylalanine methyl ester,4-Nitro-D-phenylalanine, 4-Nitro-L-phenylalanine,4-Nitro-DL-phenylalanine, (S)-(+)-4-Nitrophenylalanine methyl ester,2-(Trifluoromethyl)-D-phenylalanine,2-(Trifluoromethyl)-L-phenylalanine,3-(Trifluoromethyl)-D-phenylalanine,3-(Trifluoromethyl)-L-phenylalanine,4-(Trifluoromethyl)-D-phenylalanine, 3,3′,5-Triiodo-L-thyronine,(R)-4-bromo-β-Phe-OH, N-Acetyl-DL-β-phenylalanine, (S)-4-bromo-3-Phe-OH,(R)-4-chloro-β-Homophe-OH, (S)-4-chloro-3-Homophe-OH,(R)-4-chloro-J-Phe-OH, (S)-4-chloro-β-Phe-OH, (5)-2-cyano-β-Homophe-OH,(R)-4-cyano-β-Homophe-OH, (S)-4-cyano-β-Homophe-OH,(R)-3-cyano-β-Phe-OH, (R)-4-cyano-3-Phe-OH, (S)-4-cyano-β-Phe-OH,(R)-3,4-dimethoxy-β-Phe-OH, (S)-3,4-dimethoxy-β-Phe-OH,(R)-4-fluoro-β-Phe-OH, (S)-4-fluoro-β-Phe-OH, (S)-4-iodo-β-Homophe-OH,(S)-3-cyano-β-Homophe-OH, (S)-3,4-difluoro-β-Homophe-OH,(R)-4-fluoro-β-Homophe-OH, (S)-β2-homophenylalanine,(R)-3-methoxy-β-Phe-OH, (S)-3-methoxy-β-Phe-OH, (R)-4-methoxy-β-Phe-OH,(S)-4-methyl-β-Homophe-OH, (R)-2-methyl-β-Phe-OH, (S)-2-methyl-β-Phe-OH,(R)-3-methyl-β-Phe-OH, (S)-3-methyl-β-Phe-OH, (R)-4-methyl-β-Phe-OH,(S)-4-methyl-β-Phe-OH, β-Phe-OH, D-β-Phe-OH,(S)-2-(trifluoromethyl)-β-Homophe-OH,(S)-2-(trifluoromethyl)-β-Homophe-OH,(S)-3-(trifluoromethyl)-β-Homophe-OH,(R)-4-(trifluoromethyl)-β-Homophe-OH, (S)-2-(trifluoromethyl)-β-Phe-OH,(R)-3-(trifluoromethyl)-β-Phe-OH, (S)-3-(trifluoromethyl)-β-Phe-OH,(R)-4-(trifluoromethyl)-β-Phe-OH, (S)-4-(trifluoromethyl)-β-Phe-OH,β-Homophe-OH, D-β-Homophe-OH, (S)-2-methyl-β-Homophe-OH,(S)-3-methyl-β-Homophe-OH, β-Phe-OH, β-D-Phe-OH,(S)-3-(trifluoromethyl)-β-Homophe-OH, L-β-Homophenylalanine,DL-β-Homophenylalanine, DL-β3-Phenylalanine, DL-homophenylalanine methylester, D-Homophenylalanine, L-Homophenylalanine, DL-Homophenylalanine,D-Homophenylalanine ethyl ester, (R)-β²-homophenylalanine,L-α-methyl-homophenylalanine [Mhphe], L-α-methylphenylalanine [Mphe],D-α-methylphenylalanine [Dmphe], L-N-methyl-homophenylalanine [Nm phe],L-homophenylalanine [Hphe], L-N-methylphenylalanine [Nmphe],D-N-methylphenylalanine [Dnmphe], N-benzylglycine [Nphe] andD-phenylalanine [Dphe, (dF), f]. Each possibility represents a separateembodiment.

Non limiting examples for proline non-conservative amino acids are:homoproline (hPro), (4-hydroxy)Pro (4HyP), (3-hydroxy)Pro (3HyP),gamma-benzyl-proline, gamma-(2-fluoro-benzyl)-proline,gamma-(3-fluoro-benzyl)-proline, gamma-(4-fluoro-benzyl)-proline,gamma-(2-chloro-benzyl)-proline, gamma-(3-chloro-benzyl)-proline,gamma-(4-chloro-benzyl)-proline, gamma-(2-bromo-benzyl)-proline,gamma-(3-bromo-benzyl)-proline, gamma-(4-bromo-benzyl)-proline,gamma-(2-methyl-benzyl)-proline, gamma-(3-methyl-benzyl)-proline,gamma-(4-methyl-benzyl)-proline, gamma-(2-nitro-benzyl)-proline,gamma-(3-nitro-benzyl)-proline, gamma-(4-nitro-benzyl)-proline,gamma-(l-naphthalenylmethyl)-proline,gamma-(2-naphthalenylmethyl)-proline,gamma-(2,4-dichloro-benzyl)-proline,gamma-(3,4-dichloro-benzyl)-proline,gamma-(3,4-difluoro-benzyl)-proline,gamma-(2-trifluoro-methyl-benzyl)-proline,gamma-(3-trifluoro-methyl-benzyl)-proline,gamma-(4-trifluoro-methyl-benzyl)-proline,gamma-(2-cyano-benzyl)-proline, gamma-(3-cyano-benzyl)-proline,gamma-(4-cyano-benzyl)-proline, gamma-(2-iodo-benzyl)-proline,gamma-(3-iodo-benzyl)-proline, gamma-(4-iodo-benzyl)-proline,gamma-(3-phenyl-allyl-benzyl)-proline,gamma-(3-phenyl-propyl-benzyl)-proline,gamma-(4-tert-butyl-benzyl)-proline, gamma-benzhydryl-proline,gamma-(4-biphenyl-methyl)-proline, gamma-(4-thiazolyl-methyl)-proline,gamma-(3-benzothienyl-methyl)-proline, gamma-(2-thienyl-methyl)-proline,gamma-(3-thienyl-methyl)-proline, gamma-(2-furanyl-methyl)-proline,gamma-(2-pyridinyl-methyl)-proline, gamma-(3-pyridinyl-methyl)-proline,gamma-(4-pyridinyl-methyl)-proline, gamma-allyl-proline,gamma-propynyl-proline, alpha-modified-proline residues, pipecolic acid,azetidine-3-carboxylicacid, L-β-Homoproline, L-β³-homoproline,L-β-Homohydroxyproline, hydroxyproline [Hyp], L-α-methylproline [Mpro],D-α-methylproline [Dmpro], L-N-methylproline [Nmpro], D-N-methylproline[Dnmpro], and D-proline [Dpro, (dP), p]. Each possibility represents aseparate embodiment.

Non limiting examples for serine non-conservative amino acids are:(2R,3S)-3-phenylisoserine, D-cycloserine, L-Isoserine, DL-Isoserine,DL-3-Phenylserine, L-β-Homoserine, D-Homoserine, D-Homoserine,L-3-Homoserine, L-homoserine, L-α-methylserine [Mser], D-α-methylserine[Dmser], L-N-methylserine [Nmser], D-N-methylserine [Dnmser], D-serine[Dser, (dS), s], N-(hydroxymethyl)glycine [Nser] and phosphoserine[pSer]. Each possibility represents a separate embodiment.

Non limiting examples for threonine non-conservative amino acids are:L-allo-Threonine, D-Thyroxine, L-p-Homothreonine, L-α-methylthreonine[Mthr], D-α-methylthreonine [Dmthr], L-N-methylthreonine [Nmthr],D-N-methylthreonine [Dnmthr], D-threonine [Dthr, (dT), t],N-(1-hydroxyethyl)glycine [Nthr] and phosphothreonine [pThr]. Eachpossibility represents a separate embodiment.

Non limiting examples for tryptophan non-conservative amino acids are:5-Fluoro-L-tryptophan, 5-Fluoro-DL-tryptophan, 5-Hydroxy-L-tryptophan,5-Methoxy-DL-tryptophan, L-abrine, 5-Methyl-DL-tryptophan, H-Tpi-OMe.β-Homotrp-OMe, L-β-Homotryptophan, L-α-methyltryptophan [Mtrp],D-α-methyltryptophan [Dmtrp], L-N-methyltryptophan [Nmtrp],D-N-methyltryptophan [Dnmtrp], N-(3-indolylethyl)glycine [Nhtrp],D-tryptophan [Dtrp, (dW), w]. Each possibility represents a separateembodiment.

Non limiting examples for tyrosine non-conservative amino acids are: 3,5diiodotyrosine (3,5-dITyr), 3,5 diBromotyrosine (3,5-dBTyr),homotyrosine, D-tyrosine, 3-amino-L-tyrosine, 3-amino-D-tyrosine,3-iodo-L-tyrosine, 3-iodo-D-tyrosine, 3-methoxy-L-tyrosine,3-methoxy-D-tyrosine, L-thyroxine, D-thyroxine, L-thyronine,D-thyronine, O-methyl-L-tyrosine, O-methyl-D-tyrosine, D-thyronine,O-ethyl-L-tyrosine, O-ethyl-D-tyrosine, 3,5,3′-triiodo-L-thyronine,3,5,3′-triiodo-D-thyronine, 3,5-diiodo-L-thyronine,3,5-diiodo-D-thyronine, D-meta-tyrosine, L-meta-tyrosine,D-ortho-tyrosine, L-ortho-tyrosine, phenylalanine, substitutedphaenylalanine, N-nitro phenylalanine, p-nitro phenylalanine,3-chloro-Dtyr-oh, Tyr(3,5-diI), 3-Chloro-L-tyrosine, Tyr(3-NO₂)—OH,Tyr(3,5-diI)—OH, N-Me-Tyr-OH, α-Methyl-DL-tyrosine, 3-Nitro-L-tyrosine,DL-o-Tyrosine, β-Homotyr-OH, (R)-β-Tyr-OH, (S)-β-Tyr-OH,L-α-methyltyrosine [Mtyr], D-α-methyltyrosine [Dmtyr],L-N-methyltyrosine [Nmtyr], D-N-methyltyrosine [Dnmtyr], D-tyrosine[Dtyr, (dY), y], O-methyl-tyrosine, and phosphotyrosine [pTyr]. Eachpossibility represents a separate embodiment.

Non limiting examples for valine non-conservative amino acids are:3-Fluoro-DL-valine, 4,4,4,4′,4′,4′-Hexafluoro-DL-valine, D-valine [Dval,(dV), v], N-Me-Val-OH [Nmval], N-Me-Val-OH, L-α-methylvaline [Mval],D-α-methylvaline [Dmval], (R)-(+)-α-Methylvaline, (S)-(−)-α-Methylvalineand D-N-methylvaline [Dnmval]. Each possibility represents a separateembodiment.

Other non-natural amino acids that may be substituted asnon-conservative replacements include: Ornithine and its modifications:D-Ornithine [Dorn], L-Ornithine [Orn], DL-Ornithine, L-α-methylornithine[Morn], D-α-methylornithine [Dmorn], L-N-methylornithine [Nmorn],D-N-methylornithine [Dnmorn] and N-(3-aminopropyl)glycine [Norn]. Eachpossibility represents a separate embodiment.

Alicyclic amino acids: L-2,4-Diaminobutyric acid, L-2,3-DiaminopropionicAcid, N-Me-Aib-OH, (R)-2-(amino)-5-hexynoic acid,piperidine-2-carboxylic acid, aminonorbornyl-carboxylate [Norb],alpha-aminobutyric acid [Abu], aminocyclopropane-carboxylate [Cpro],(cis)-3-Aminobicyclo[2.2.1]heptane-2-carboxylic acid,exo-cis-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid,1-Amino-1-cyclobutanecarboxylic acid, cis-2-Aminocycloheptanecarboxylicacid, 1-Aminocyclohexanecarboxylic acid,cis-2-Aminocyclohexanecarboxylic acid,trans-2-Aminocyclohexanecarboxylic acid,cis-6-Amino-3-cyclohexene-1-carboxylic acid, 2-(1-Aminocyclohexyl)aceticacid, cis-2-Amino-1-cyclooctanecarboxylic acid,cis-2-Amino-3-cyclooctene-1-carboxylic acid,(1R,2S)-(−)-2-Amino-1-cyclopentanecarboxylic acid,(1S,2R)-(+)-2-Amino-1-cyclopentanecarboxylic acid,cis-2-Amino-1-cyclopentanecarboxylic acid, 2-(1-Aminocyclopentyl)aceticacid, cis-2-Amino-2-methylcyclohexanecarboxylic acid,cis-2-Amino-2-methylcyclopentanecarboxylic acid,3-Amino-3-(4-nitrophenyl)propionic acid, 3-Azetidinecarboxylic acid,amchc-oh, 1-aminocyclobutane carboxylic acid,1-(amino)cyclohexanecarboxylic acid, cis-2-(amino)-cyclohexanecarboxylicacid, trans-2-(amino)-cyclohexanecarboxylic acid,cis-4-(amino)cyclohexanecarboxylic acid,trans-4-(amino)cyclohexanecarboxylic acid,(±)-cis-2-(amino)-3-cyclohexene-1-carboxylic acid,(±)-cis-6-(amino)-3-cyclohexene-1-carboxylic acid,2-(1-aminocyclohexyl)acetic acid, cis-[4-(amino)cyclohexyl]acetic acid,1-(amino)cyclopentanecarboxylic acid,(±)-cis-2-(amino)cyclopentanecarboxylic acid,(1R,4S)-(+)-4-(amino)-2-cyclopentene-1-carboxylic acid,(±)-cis-2-(amino)-3-cyclopentene-1-carboxylic acid,2-(1-aminocyclopentyl)acetic acid, 1-(amino)cyclopropanecarboxylic acid,Ethyl 1-aminocyclopropanecarboxylate, 1,2-trans-achec-oh,1-(amino)cyclobutanecarboxylic acid, 1-(amino)cyclohexanecarboxylicacid, cis-2-(amino)-cyclohexanecarboxylic acid,trans-2-(amino)cyclohexanecarboxylic acid,cis-4-(amino)cyclohexanecarboxylic acid,trans-4-(amino)cyclohexanecarboxylic acid,cis-[4-(amino)cyclohexyl]acetic acid, 1-(amino)cyclopentanecarboxylicacid, (1R,4S)-(+)-4-(amino)-2-cyclopentene-1-carboxylic acid,(1S,4R)-(−)-4-(amino)-2-cyclopentene-1-carboxylic acid,1-(amino)cyclopropanecarboxylic acid,trans-4-(aminomethyl)cyclohexanecarboxylic acid, D-Dab-OH,3-Amino-3-(3-bromophenyl)propionic acid, 3-Aminobutanoic acid,cis-2-Amino-3-cyclopentene-1-carboxylic acid, DL-3-Aminoisobutyric acid,(R)-3-Amino-2-phenylpropionic acid,(±)-3-(amino)-4-(4-biphenylyl)butyric acid,cis-3-(amino)cyclohexanecarboxylic acid,(1S,3R)-(+)-3-(amino)cyclopentanecarboxylic acid,(2R,3R)-3-(amino)-2-hydroxy-4-phenylbutyric acid,(2S,3R)-3-(amino)-2-hydroxy-4-phenylbutyric acid,2-(aminomethyl)phenylacetic acid, (R)-3-(amino)-2-methylpropionic acid,(S)-3-(amino)-2-methylpropionic acid,(R)-3-(amino)-4-(2-naphthyl)butyric acid,(S)-3-(amino)-4-(2-naphthyl)butyric acid,(R)-3-(amino)-5-phenylpentanoic acid, (R)-3-(amino)-2-phenylpropionicacid, Ethyl 3-(benzylamino)propionate,cis-3-(amino)cyclohexanecarboxylic acid, (S)-3-(amino)-5-hexenoic acid,(R)-3-(amino)-2-methylpropionic acid, (S)-3-(amino)-2-methylpropionicacid, (R)-3-(amino)-4-(2-naphthyl)butyric acid,(S)-3-(amino)-4-(2-naphthyl)butyric acid,(R)-(−)-Pyrrolidine-3-carboxylic acid, (S)-(+)-Pyrrolidine-3-carboxylicacid, N-methyl-γ-aminobutyrate [Nmgabu], γ-aminobutyric acid [Gabu],N-methyl-α-amino-α-methylbutyrate [Nmaabu], α-amino-α-methylbutyrate[Aabu], N-methyl-α-aminoisobutyrate [Nmaib], α-aminoisobutyric acid[Aib], α-methyl-y-aminobutyrate [Mgabu]. Each possibility represents aseparate embodiment.

Phenyl glycine and its modifications: Phg-OH, D-Phg-OH,2-(piperazino)-2-(3,4-dimethoxyphenyl)acetic acid,2-(piperazino)-2-(2-fluorophenyl)acetic acid,2-(4-piperazino)-2-(3-fluorophenyl)acetic acid,2-(4-piperazino)-2-(4-methoxyphenyl)acetic acid,2-(4-piperazino)-2-(3-pyridyl)acetic acid,2-(4-piperazino)-2-[4-(trifluoromethyl)phenyl]acetic acid,L-(+)-2-Chlorophenylglycine, (±)-2-Chlorophenylglycine,(±)-4-Chlorophenylglycine, (R)-(−)-2-(2,5-Dihydrophenyl)glycine,(R)-(−)-N-(3,5-Dinitrobenzoyl)-α-phenylglycine,(S)-(+)-N-(3,5-Dinitrobenzoyl)-α-phenylglycine, 2,2-Diphenylglycine,2-Fluoro-DL-α-phenylglycine, 4-Fluoro-D-α-phenylglycine,4-Hydroxy-D-phenylglycine, 4-Hydroxy-L-phenylglycine, 2-Phenylglycine,D-(−)-α-Phenylglycine, D-(−)-α-Phenylglycine, DL-α-Phenylglycine,L-(+)-α-Phenylglycine, N-Phenylglycine, (R)-(−)-2-Phenylglycine methylester, (S)-(+)-2-Phenylglycine methyl ester, 2-Phenylglycinonitrilehydrochloride, α-Phenylglycinonitrile,3-(Trifluoromethyl)-DL-phenylglycine, and4-(Trifluoromethyl)-L-phenylglycine. Each possibility represents aseparate embodiment.

Penicillamine and its modifications: N-Acetyl-D-penicillamine,D-Penicillamine, L-Penicillamine [Pen], DL-Penicillamine.α-methylpenicillamine [Mpen], N-methylpenicillamine [Nmpen]. Eachpossibility represents a separate embodiment.

β-Homopyrrolidine. Each possibility represents a separate embodiment.

Aromatic amino acids: 3-Acetamidobenzoic acid, 4-Acetamidobenzoic acid,4-Acetamido-2-methylbenzoic acid, N-Acetylanthranilic acid,3-Aminobenzoic acid, 3-Aminobenzoic acid hydrochloride, 4-Aminobenzoicacid, 4-Aminobenzoic acid, 4-Aminobenzoic acid, 4-Aminobenzoic acid,4-Aminobenzoic acid, 4-Aminobenzoic acid,2-Aminobenzophenone-2′-carboxylic acid, 2-Amino-4-bromobenzoic acid,2-Amino-5-bromobenzoic acid, 3-Amino-2-bromobenzoic acid,3-Amino-4-bromobenzoic acid, 3-Amino-5-bromobenzoic acid,4-Amino-3-bromobenzoic acid, 5-Amino-2-bromobenzoic acid,2-Amino-3-bromo-5-methylbenzoic acid, 2-Amino-3-chlorobenzoic acid,2-Amino-4-chlorobenzoic acid, 2-Amino-5-chlorobenzoic acid,2-Amino-5-chlorobenzoic acid, 2-Amino-6-chlorobenzoic acid,3-Amino-2-chlorobenzoic acid, 3-Amino-4-chlorobenzoic acid,4-Amino-2-chlorobenzoic acid, 4-Amino-3-chlorobenzoic acid,5-Amino-2-chlorobenzoic acid, 5-Amino-2-chlorobenzoic acid,4-Amino-5-chloro-2-methoxybenzoic acid, 2-Amino-5-chloro-3-methylbenzoicacid, 3-Amino-2,5-dichlorobenzoic acid, 4-Amino-3,5-dichlorobenzoicacid, 2-Amino-4,5-dimethoxybenzoic acid, 4-(2-Aminoethyl)benzoic acidhydrochloride, 2-Amino-4-fluorobenzoic acid, 2-Amino-5-fluorobenzoicacid, 2-Amino-6-fluorobenzoic acid, 4-Amino-2-fluorobenzoic acid,2-Amino-5-hydroxybenzoic acid, 3-Amino-4-hydroxybenzoic acid,4-Amino-3-hydroxybenzoic acid, 2-Amino-5-iodobenzoic acid,5-Aminoisophthalic acid, 2-Amino-3-methoxybenzoic acid,2-Amino-4-methoxybenzoic acid, 2-Amino-5-methoxybenzoic acid,3-Amino-2-methoxybenzoic acid, 3-Amino-4-methoxybenzoic acid,3-Amino-5-methoxybenzoic acid, 4-Amino-2-methoxybenzoic acid,4-Amino-3-methoxybenzoic acid, 5-Amino-2-methoxybenzoic acid,2-Amino-3-methylbenzoic acid, 2-Amino-5-methylbenzoic acid,2-Amino-6-methylbenzoic acid, 3-(Aminomethyl)benzoic acid,3-Amino-2-methylbenzoic acid, 3-Amino-4-methylbenzoic acid,4-(Aminomethyl)benzoic acid, 4-Amino-2-methylbenzoic acid,4-Amino-3-methylbenzoic acid, 5-Amino-2-methylbenzoic acid,3-Amino-2-naphthoic acid, 6-Amino-2-naphthoic acid,2-Amino-3-nitrobenzoic acid, 2-Amino-5-nitrobenzoic acid,2-Amino-5-nitrobenzoic acid, 4-Amino-3-nitrobenzoic acid,5-Amino-2-nitrobenzoic acid, 3-(4-Aminophenyl)propionic acid,3-Aminophthalic acid, 4-Aminophthalic acid, 3-Aminosalicylic acid,4-Aminosalicylic acid, 5-Aminosalicylic acid, 5-Aminosalicylic acid,2-Aminoterephthalic acid, 2-Amino-3,4,5,6-tetrafluorobenzoic acid,4-Amino-2,3,5,6-tetrafluorobenzoic acid,(R)-2-Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid,(S)-2-Amino-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid,2-Amino-3-(trifluoromethyl)benzoic acid,2-Amino-3-(trifluoromethyl)benzoic acid,3-Amino-5-(trifluoromethyl)benzoic acid,5-Amino-2,4,6-triiodoisophthalic acid, 2-Amino-3,4,5-trimethoxybenzoicacid, 2-Anilinophenylacetic acid, 2-Abz-OH, 3-Abz-OH, 4-Abz-OH,2-(aminomethyl)benzoic acid, 3-(aminomethyl)benzoic acid,4-(aminomethyl)benzoic acid, tert-Butyl 2-aminobenzoate, tert-Butyl3-aminobenzoate, tert-Butyl 4-aminobenzoate, 4-(Butylamino)benzoic acid,2,3-Diaminobenzoic acid, 3,4-Diaminobenzoic acid, 3,5-Diaminobenzoicacid, 3,5-Diaminobenzoic acid, 3,5-Dichloroanthranilic acid,4-(Diethylamino)benzoic acid, 4,5-Difluoroanthranilic acid,4-(Dimethylamino)benzoic acid, 4-(Dimethylamino)benzoic acid,3,5-Dimethylanthranilic acid, 5-Fluoro-2-methoxybenzoic acid, 2-Abz-OH,3-Abz-OH, 4-Abz-OH, 3-(aminomethyl)benzoic acid, 4-(aminomethyl)benzoicacid, 4-(2-hydrazino)benzoic acid, 3-Hydroxyanthranilic acid,3-Hydroxyanthranilic acid, Methyl 3-aminobenzoate,3-(Methylamino)benzoic acid, 4-(Methylamino)benzoic acid, Methyl2-amino-4-chlorobenzoate, Methyl 2-amino-4,5-dimethoxybenzoate,4-Nitroanthranilic acid, N-Phenylanthranilic acid, N-Phenylanthranilicacid, and Sodium 4-aminosalicylate. Each possibility represents aseparate embodiment.

Other amino acids: (S)-α-Amino-γ-butyrolactone, DL-2-Aminocaprylic acid,7-Aminocephalosporanic acid, 4-Aminocinnamic acid,(S)-(+)-α-Aminocyclohexanepropionic acid,(R)-Amino-(4-hydroxyphenyl)acetic acid methyl ester, 5-Aminolevulinicacid, 4-Amino-nicotinic acid, 3-Aminophenylacetic acid,4-Aminophenylacetic acid, 2-Amino-2-phenylbutyric acid,4-(4-Aminophenyl)butyric acid, 2-(4-Aminophenylthio)acetic acid,DL-α-Amino-2-thiopheneacetic acid, 5-Aminovaleric acid, 8-Benzyl(S)-2-aminooctanedioate, 4-(amino)-1-methylpyrrole-2-carboxylic acid,4-(amino)tetrahydrothiopyran-4-carboxylic acid,(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid,L-azetidine-2-carboxylic acid, azetidine-3-carboxylic acid,4-(amino)piperidine-4-carboxylic acid, diaminoacetic acid, Inp-OH,(R)-Nip-OH, (S)-4-oxopiperidine-2-carboxylic acid,2-(4-piperazino)-2-(4-fluorophenyl)acetic acid,2-(4-piperazino)-2-phenylacetic acid, 4-piperidineacetaldehyde,4-piperidylacetic acid, (−)-L-thioproline, Tle-OH,3-piperidinecarboxylic acid, L-(+)-Canavanine, (±)-Carnitine,Chlorambucil, 2,6-Diaminopimelic acid, meso-2,3-Diaminosuccinic acid,4-(Dimethylamino)cinnamic acid, 4-(Dimethylamino)phenylacetic acid,Ethyl (S)—N-Boc-piperidine-3-carboxylate, Ethyl piperazinoacetate,4-[2-(amino)ethyl]piperazin-1-ylacetic acid,(R)-4-(amino)-5-phenylpentanoic acid, (S)-azetidine-2-carboxylic acid,azetidine-3-carboxylic acid, guvacine, Inp-OH, (R)-Nip-OH, DL-Nip-OH,4-phenyl-piperidine-4-carboxylic acid, 1-piperazineacetic acid,4-piperidineacetic acid, (R)-piperidine-2-carboxylic acid,(S)-piperidine-2-carboxylic acid,(S)-1,2,3,4-tetrahydronorharmane-3-carboxylic acid, Tic-OH, D-Tic-OH,Iminodiacetic acid, Indoline-2-carboxylic acid, DL-Kynurenine,L-aziridine-2-carboxylate, Methyl 4-aminobutyrate,(S)-2-Piperazinecarboxylic acid, 2-(1-Piperazinyl)acetic acid,(R)-(−)-3-Piperidinecarboxylic acid, 2-Pyrrolidone-5-carboxylic acid,(R)-(+)-2-Pyrrolidone-5-carboxylic acid,(R)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid,(S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid,L-4-Thiazolidinecarboxylic acid,(4R)-(−)-2-Thioxo-4-thiazolidinecarboxylic acid, hydrazinoacetic acid,and 3,3′,5-Triiodo-L-thyronine. Each possibility represents a separateembodiment.

The present disclosure provides peptides comprising peptidomimeticcompounds having further improved stability and cell permeabilityproperties. Some embodiments comprise a peptide according to any of SEQID NO: 1-213, 230-236 and 239, wherein one of more peptide bonds(—CO—NH—) within the peptide may be substituted, for example, byN-methylated amide bonds (—N(CH₃)—CO—), ester bonds (—C(═O)—O—),ketomethylene bonds (—CO—CH₂—), sulfinylmethylene bonds (—S(═O)—CH₂—),α-aza bonds (—NH—N(R)—CO—), wherein R is any alkyl (e.g., methyl), aminebonds (—CH₂—NH—), sulfide bonds (—CH₂—S—), ethylene bonds (—CH₂—CH₂—),hydroxyethylene bonds (—CH(OH)—CH2-), thioamide bonds (—CS—NH—),olefinic double bonds (—CH═CH—), fluorinated olefinic double bonds(—CF═CH—), or retro amide bonds (—NH—CO—), peptide derivatives(—N(R^(x))—CH₂—CO—), wherein R^(x) is the “normal” side chain, naturallypresent on the carbon atom. These modifications can occur at any of thebonds along the peptide chain and even at several (2-3) bonds at thesame time.

The peptides of some embodiments are preferably utilized in a linearform, although it will be appreciated that in cases where cyclizationdoes not severely interfere with peptide characteristics, cyclic formsof the peptide can also be utilized and are contemplated as embodiments.

In exemplary embodiments, the peptide comprises any integer number ofamino acids from 4 to 50, inclusive, connected via peptide bonds. Forpurposes of describing exemplary genera of peptides by size, all integersize ranges within the range of 4 to 50 amino acids are specificallycontemplated. In some exemplary embodiments, the peptide comprises atleast seven or eight amino acids connected via peptide bonds. Inexemplary aspects, the peptide is at least about 4 amino acids inlength, about 5 amino acids in length, about 6 amino acids in length,about 7 amino acids in length, or about 8 amino acids in length. Inexemplary aspects, the peptide is at least about 9 amino acids inlength, about 10 amino acids in length, about 11 amino acids in length,or about 12 amino acids in length. In exemplary aspects, the peptide isless than about 50 amino acids in length, less than about 40 aminoacids, or less than about 30 amino acids, less than about 25 amino acidsin length, or less than about 20 amino acids in length. In exemplaryaspects, the peptide is about 4 to about 30 amino acids in length orabout 5 to about 20 amino acids in length. In exemplary aspects, thepeptide is about 6 to about 10 amino acids in length, about 5 to about20 amino acids in length, about 4 to about 30 amino acids in length, orabout 6 to about 16 amino acids in length. In exemplary aspects, thepeptide is 4-5, 6-7, 7-8, 9-10, 11-12, 13-15, 14-15, 14-16, 15-16,16-18, 16-19, 17-19, 18-19, 20-22, 22-24, 23-24, or 24-25 amino acids inlength. In some embodiments, the peptide is a 4-mer, 5-mer, 6-mer,7-mer, 8-mer, 9-mer, 10-mer, 11-mer, 12-mer, 13-mer, 14-mer, 15-mer,16-mer, 17-mer, or 18-mer.

It is yet another object of the present invention to provide peptidescomprising peptidomimetic compounds having further improved stabilityand cell permeability properties. Some embodiments of the inventioncomprises a peptide according to any of SEQ ID NO: 1-213, 230-236 and239, wherein said peptide bonds (—CO—NH—) within the peptide may besubstituted, for example, by N-methylated amide bonds (N-Me;—N(CH₃)—CO—), ester bonds (—C(═O)—O—), ketomethylene bonds (—CO—CH₂—),sulfinylmethylene bonds (—S(═O)—CH₂—), α-aza bonds (—NH—N(R)—CO—),wherein R is any alkyl (e.g., methyl), amine bonds (—CH₂—NH—), sulfidebonds (—CH₂—S—), ethylene bonds (—CH₂—CH₂—), hydroxyethylene bonds(—CH(OH)—CH₂—), thioamide bonds (—CS—NH—), olefinic double bonds(—CH═CH—), fluorinated olefinic double bonds (—CF═CH—), or retro amidebonds (—NH—CO—), peptide derivatives (—N(R^(x))—CH₂—CO—), wherein R^(x)is the “normal” side chain, naturally present on the carbon atom. Thesemodifications can occur at any of the bonds along the peptide chain andeven at several (2-3) bonds at the same time.

The present invention further provides conjugates comprising any of thepeptides and analogs described herein conjugated to a moiety forextending half life or increasing cell penetration. For example, thehalf life extending moiety is a peptide or protein and the conjugate isa fusion peptide or chimeric peptide. Alternatively, the half lifeextending moiety is a polymer, e.g., a polyethylene glycol. The presentdisclosure furthermore provides dimers and multimers comprising any ofthe peptides and analogs described herein. Any moiety known in the artto facilitate actively or passively or enhance permeability of thecompound into cells may be used for conjugation with the peptide coreaccording to the present invention. Non-limitative examples include:hydrophobic moieties such as fatty acids, steroids and bulky aromatic oraliphatic compounds; moieties which may have cell-membrane receptors orcarriers, such as steroids, vitamins and sugars, natural and non-naturalamino acids and transporter peptides. According to a preferredembodiment, the hydrophobic moiety is a lipid moiety or an amino acidmoiety. The permeability-enhancing moiety may be connected to anyposition in the peptide moiety, directly or through a spacer or linker,preferably to the amino terminus of the peptide moiety. The hydrophobicmoiety according to the invention may preferably comprise a lipid moietyor an amino acid moiety. According to a specific embodiment thehydrophobic moiety is selected from the group consisting of:phospholipids, steroids, sphingosines, ceramides, octyl-glycine,2-cyclohexylalanine, benzolylphenylalanine, propionoyl (C₃); butanoyl(C₄); pentanoyl (C₅); caproyl (C₆); heptanoyl (C₇); capryloyl (C₈);nonanoyl (C₉); capryl (C₁₀); undecanoyl (C₁₁); lauroyl (C₁₂);tridecanoyl (C₁₃); myristoyl (C₁₄); pentadecanoyl (C₁₅); palmitoyl(C₁₆); phtanoyl ((CH₃)₄); heptadecanoyl (C₁₆); stearoyl (C₁₈);nonadecanoyl (C₁₉); arachidoyl (C₂₀); heniecosanoyl (C₂₁); behenoyl(C₂₂); trucisanoyl (C₂₃); and lignoceroyl (C₂₄); wherein saidhydrophobic moiety is attached to said chimeric peptide or polypeptidewith amide bonds, sulfhydryls, amines, alcohols, phenolic groups, orcarbon-carbon bonds. Other examples for lipidic moieties which may beused according to the present invention: Lipofectamine, Transfectace,Transfectam, Cytofectin, DMRIE, DLRIE, GAP-DLRIE, DOTAP, DOPE, DMEAP,DODMP, DOPC, DDAB, DOSPA, EDLPC, EDMPC, DPH, TMADPH, CTAB, lysyl-PE,DC-Cho, -alanyl cholesterol; DCGS, DPPES, DCPE, DMAP, DMPE, DOGS, DOHME,DPEPC, Pluronic, Tween, BRU, plasmalogen, phosphatidylethanolamine,phosphatidylcholine, glycerol-3-ethylphosphatidylcholine, dimethylammonium propane, trimethyl ammonium propane, diethylammonium propane,triethylammonium propane, dimethyldioctadecylammonium bromide, asphingolipid, sphingomyelin, a lysolipid, a glycolipid, a sulfatide, aglycosphingolipid, cholesterol, cholesterol ester, cholesterol salt,oil, N-succinyldioleoylphosphatidylethanolamine,1,2-dioleoyl-sn-glycerol, 1,3-dipalmitoyl-2-succinylglycerol,1,2-dipalmitoyl-sn-3-succinylglycerol,1-hexadecyl-2-palmitoylglycerophosphatidylethanolamine,palmitoylhomocystiene, N,N′-Bis(dodecyaminocarbonylmethylene)-N,N′-bis((-N,N,N-trimethylammoniumethyl-aminocarbonylmethylene)ethylenediamine tetraiodide;N,N″-Bis(hexadecylaminocarbonylmethylene)-N,N′,N″-tris((-N,N,N-trimethylammonium-ethylaminocarbonylmethylenediethylenetriaminehexaiodide;N,N′-Bis(dodecylaminocarbonylmethylene)-N,N″-bis((-N,N,N-trimethylammoniumethylaminocarbonylmethylene)cyclohexylene-1,4-diamine tetraiodide;1,7,7-tetra-((-N,N,N,N-tetramethylammoniumethylamino-carbonylmethylene)-3-hexadecylarninocarbonyl-methylene-1,3,7-triaazaheptaneheptaiodide;N,N,N′,N′-tetra((-N,N,N-trimethylammonium-ethylaminocarbonylmethylene)-N′-(1,2-dioleoylglycero-3-phosphoethanolaminocarbonylmethylene)diethylenetriamine tetraiodide;dioleoylphosphatidylethanolamine, a fatty acid, a lysolipid,phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine,phosphatidylglycerol, phosphatidylinositol, a sphingolipid, aglycolipid, a glucolipid, a sulfatide, a glycosphingolipid, phosphatidicacid, palmitic acid, stearic acid, arachidonic acid, oleic acid, a lipidbearing a polymer, a lipid bearing a sulfonated saccharide, cholesterol,tocopherol hemisuccinate, a lipid with an ether-linked fatty acid, alipid with an ester-linked fatty acid, a polymerized lipid, diacetylphosphate, stearylamine, cardiolipin, a phospholipid with a fatty acidof 6-8 carbons in length, a phospholipid with asymmetric acyl chains,6-(5-cholesten-3b-yloxy)-l-thio-b-D-galactopyranoside,digalactosyldiglyceride,6-(5-cholesten-3b-yloxy)hexyl-6-amino-6-deoxy-1-thio-b-D-galactopyranoside,6-(5-cholesten-3b-yloxy)hexyl-6-amino-6-deoxyl-1-thio-a-D-mannopyranoside,12-(((7′-diethylamino-coumarin-3-yl)carbonyl)methylamino)-octadecanoicacid; N-[12-(((7′-diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadecanoyl]-2-aminopalmitic acid;cholesteryl)4′-trimethyl-ammonio)butanoate;N-succinyldioleoyl-phosphatidylethanolamine; 1,2-dioleoyl-sn-glycerol;1,2-dipalmitoyl-sn-3-succinyl-glycerol;1,3-dipalmitoyl-2-succinylglycerol,l-hexadecyl-2-palmitoylglycero-phosphoethanolamine, andpalmitoylhomocysteine.

The peptides of the present invention may be attached (either covalentlyor non-covalently) to a penetrating agent. As used herein the phrase“penetrating agent” refers to an agent which enhances translocation ofany of the attached peptide across a cell membrane. Typically, peptidebased penetrating agents have an amino acid composition containingeither a high relative abundance of positively charged amino acids suchas lysine or arginine, or have sequences that contain an alternatingpattern of polar/charged amino acids and non-polar, hydrophobic aminoacids. By way of a non-limiting example, cell penetrating peptide (CPP)sequences may be used in order to enhance intracellular penetration.CPPs may include short and long versions of the protein transductiondomain (PTD) of HIV TAT protein, such as for example, YARAAARQARA (SEQID NO: 214), YGRKKRR (SEQ ID NO: 215), YGRKKRRQRRR (SEQ ID NO: 216), orRRQRR (SEQ ID NO: 217)]. However, the disclosure is not so limited, andany suitable penetrating agent may be used, as known by those of skillin the art. Another method of enhancing cell penetration is viaN-terminal myristoilation. In this protein modification, a myristoylgroup (derived from myristic acid) is covalently attached via an amidebond to the alpha-amino group of an N-terminal amino acid of thepeptide. Some technologies are described in. Soriaga, et al. “A DesignedInhibitor of p53 Aggregation Rescues p53 Tumor Suppression in OvarianCarcinomas.” Cancer Cell. 29. no. 1 (Jan. 11, 2016): 90-103. Other cellpenetrating technology includes that found in patent publicationsWO2016102339; WO2014131892; WO2016087842; WO2014041505; WO2013098337,WO2010012850; WO2014147193; WO2014001229; WO2015075747, WO2012090150,WO2014056813, WO2014009259 and WO2011157713.

According to some embodiments the peptide is modified, e.g it mayinclude a duration enhancing moiety. The duration enhancing moiety canbe a water soluble polymer, or a long chain aliphatic group. In someembodiments, a plurality of duration enhancing moieties are attached tothe peptide, in which case each linker to each duration enhancing moietyis independently selected from the linkers described herein.

According to some embodiments the amino terminus of the peptide ismodified, e.g., it may be acylated. According to additional embodimentsthe carboxy terminus is modified, e.g., it may be acylated, amidated,reduced or esterified. In accordance with some embodiments, the peptidecomprises an acylated amino acid (e.g., a non-coded acylated amino acid(e.g., an amino acid comprising an acyl group which is non-native to anaturally-occurring amino acid)). In accordance with one embodiment, thepeptide comprises an acyl group which is attached to the peptide via anester, thioester, or amide linkage for purposes of prolonging half-lifein circulation and/or delaying the onset of and/or extending theduration of action and/or improving resistance to proteases. Acylationcan be carried out at any position within the peptide, (e.g., the aminoacid at the C-terminus), provided that activity is retained, if notenhanced. The peptide in some embodiments can be acylated at the sameamino acid position where a hydrophilic moiety is linked, or at adifferent amino acid position. The acyl group can be covalently linkeddirectly to an amino acid of the peptide, or indirectly to an amino acidof the peptide via a spacer, wherein the spacer is positioned betweenthe amino acid of the peptide and the acyl group.

In specific aspects, the peptide is modified to comprise an acyl groupby direct acylation of an amine, hydroxyl, or thiol of a side chain ofan amino acid of the peptide. In this regard, the acylated peptide cancomprise the amino acid sequence of any of SEQ ID NO: 1-213, 230-236 and239, or a modified amino acid sequence thereof comprising one or more ofthe amino acid modifications described herein.

In some embodiments, the peptide comprises a spacer between the analogand the acyl group. In some embodiments, the peptide is covalently boundto the spacer, which is covalently bound to the acyl group. In someembodiments, the spacer is an amino acid comprising a side chain amine,hydroxyl, or thiol, or a dipeptide or tripeptide comprising an aminoacid comprising a side chain amine, hydroxyl, or thiol. The amino acidto which the spacer is attached can be any amino acid (e.g., a singly ordoubly α-substituted amino acid) comprising a moiety which permitslinkage to the spacer. For example, an amino acid comprising a sidechain NH₂, —OH, or —COOH (e.g., Lys, Orn, Ser, Asp, or Glu) is suitable.In some embodiments, the spacer is an amino acid comprising a side chainamine, hydroxyl, or thiol, or a dipeptide or tripeptide comprising anamino acid comprising a side chain amine, hydroxyl, or thiol. Whenacylation occurs through an amine group of a spacer, the acylation canoccur through the alpha amine of the amino acid or a side chain amine.In the instance in which the alpha amine is acylated, the amino acid ofthe spacer can be any amino acid. For example, the amino acid of thespacer can be a hydrophobic amino acid, e.g., Gly, Ala, Val, Leu, He,Trp, Met, Phe, Tyr, 6-amino hexanoic acid, 5-aminovaleric acid,7-aminoheptanoic acid, and 8-aminooctanoic acid. Alternatively, theamino acid of the spacer can be an acidic residue, e.g., Asp, Glu,homoglutamic acid, homocysteic acid, cysteic acid, gamma-glutamic acid.In the instance in which the side chain amine of the amino acid of thespacer is acylated, the amino acid of the spacer is an amino acidcomprising a side chain amine. In this instance, it is possible for boththe alpha amine and the side chain amine of the amino acid of the spacerto be acylated, such that the peptide is diacylated. Embodiments of theinvention include such diacylated molecules. When acylation occursthrough a hydroxyl group of a spacer, the amino acid or one of the aminoacids of the dipeptide or tripeptide can be Ser. When acylation occursthrough a thiol group of a spacer, the amino acid or one of the aminoacids of the dipeptide or tripeptide can be Cys.

In a specific embodiment, the spacer comprises an aminopoly(alkyloxy)carboxylate. In this regard, the spacer can comprise, forexample, NH₂(CH₂CH₂O)_(n)(CH₂)_(m)COOH, wherein m is any integer from 1to 6 and n is any integer from 2 to 12, such as, e.g.,8-amino-3,6-dioxaoctanoic acid, which is commercially available fromPeptides International, Inc. (Louisville, Ky.). In some embodiments, thespacer is a hydrophobic bifunctional spacer. Hydrophobic bifunctionalspacers are known in the art. See, e.g., Bioconjugate Techniques, G. T.Hermanson (Academic Press, San Diego, Calif., 1996), which isincorporated by reference in its entirety. In certain embodiments, thehydrophobic bifunctional spacer comprises two or more reactive groups,e.g., an amine, a hydroxyl, a thiol, and a carboxyl group or anycombinations thereof. In certain embodiments, the hydrophobicbifunctional spacer comprises a hydroxyl group and a carboxylate. Inother embodiments, the hydrophobic bifunctional spacer comprises anamine group and a carboxylate. In other embodiments, the hydrophobicbifunctional spacer comprises a thiol group and a carboxylate. Suitablehydrophobic bifunctional spacers comprising a carboxylate and a hydroxylgroup or a thiol group are known in the art and include, for example,8-hydroxyoctanoic acid and 8-mercaptooctanoic acid. In some embodiments,the bifunctional spacer is not a dicarboxylic acid comprising anunbranched, methylene of 1-7 carbon atoms between the carboxylategroups. In some embodiments, the bifunctional spacer is a dicarboxylicacid comprising an unbranched, methylene of 1-7 carbon atoms between thecarboxylate groups. The spacer (e.g., amino acid, dipeptide, tripeptide,hydrophilic bifunctional spacer, or hydrophobic bifunctional spacer) inspecific embodiments is 3 to 10 atoms (e.g., 6 to 10 atoms, (e.g., 6, 7,8, 9, or 10 atoms) in length. In more specific embodiments, the spaceris about 3 to 10 atoms (e.g., 6 to 10 atoms) in length and the acylgroup is a C₁₂ to C₁₈ fatty acyl group, e.g., C₁₄ fatty acyl group, C₁₆fatty acyl group, such that the total length of the spacer and acylgroup is 14 to 28 atoms, e.g., about 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, or 28 atoms. In some embodiments, the length of thespacer and acyl group is 17 to 28 (e.g., 19 to 26, 19 to 21) atoms. Inaccordance with certain foregoing embodiments, the bifunctional spacercan be a synthetic or naturally occurring amino acid (including, but notlimited to, any of those described herein) comprising an amino acidbackbone that is 3 to 10 atoms in length (e.g., 6-amino hexanoic acid,5-aminovaleric acid, 7-aminoheptanoic acid, and 8-aminooctanoic acid).Alternatively, the spacer can be a dipeptide or tripeptide spacer havinga peptide backbone that is 3 to 10 atoms (e.g., 6 to 10 atoms) inlength. Each amino acid of the dipeptide or tripeptide spacer can be thesame as or different from the other amino acid(s) of the dipeptide ortripeptide and can be independently selected from the group consistingof: naturally-occurring or coded and/or non-coded or non-naturallyoccurring amino acids, including, for example, any of the D or L isomersof the naturally-occurring amino acids (Ala, Cys, Asp, Glu, Phe, Gly,His, Ile, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, Tyr), or anyD or L isomers of the non-naturally occurring or non-coded amino acidsselected from the group consisting of: γ-alanine (β-Ala),N-α-methyl-alanine (Me-Ala), aminobutyric acid (Abu), γ-aminobutyricacid (7-Abu), aminohexanoic acid (ε-Ahx), aminoisobutyric acid (Aib),aminomethylpyrrole carboxylic acid, aminopiperidinecarboxylic acid,aminoserine (Ams), aminotetrahydropyran-4-carboxylic acid, arginineN-methoxy-N-methyl amide, β-aspartic acid (β-Asp), azetidine carboxylicacid, 3-(2-benzothiazolyl)alanine, α-tert-butylglycine,2-amino-5-ureido-n-valeric acid (citrulline, Cit), β-Cyclohexylalanine(Cha), acetamidomethyl-cysteine, diaminobutanoic acid (Dab),diaminopropionic acid (Dpr), dihydroxyphenylalanine (DOPA),dimethylthiazolidine (DMTA), γ-Glutamic acid (γ-Glu), homoserine (Hse),hydroxyproline (Hyp), isoleucine N-methoxy-N-methyl amide,methyl-isoleucine (MeIle), isonipecotic acid (Isn), methyl-leucine(MeLeu), methyl-lysine, dimethyl-lysine, trimethyl-lysine,methanoproline, methionine-sulfoxide (Met(O)), methionine-sulfone(Met(O₂)), norleucine (Nle), methyl-norleucine (Me-Nle), norvaline(Nva), ornithine (Orn), para-aminobenzoic acid (PABA), penicillamine(Pen), methylphenylalanine (MePhe), 4-Chlorophenylalanine (Phe(4-Cl)),4-fluorophenylalanine (Phe(4-F)), 4-nitrophenylalanine (Phe(4-NO₂)),4-cyanophenylalanine ((Phe(4-CN)), phenylglycine (Phg),piperidinylalanine, piperidinylglycine, 3,4-dehydroproline,pyrrolidinylalanine, sarcosine (Sar), selenocysteine (Sec),O-Benzyl-phosphoserine, 4-amino-3-hydroxy-6-methylheptanoic acid (Sta),4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA),4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA),1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid (Tic),tetrahydropyranglycine, thienylalanine (Thi), O-benzyl-phosphotyrosine,O-Phosphotyrosine, methoxytyrosine, ethoxytyrosine,O-(bis-dimethylamino-phosphono)-tyrosine, tyrosine sulfatetetrabutylamine, methyl-valine (MeVal), and alkylated3-mercaptopropionic acid. In some embodiments, the spacer comprises anoverall negative charge, e.g., comprises one or two negative-chargedamino acids. In some embodiments, the dipeptide is not any of thedipeptides of general structure A-B, wherein A is selected from thegroup consisting of Gly, Gln, Ala, Arg, Asp, Asn, Ile, Leu, Val, Phe,and Pro, wherein B is selected from the group consisting of Lys, His,Trp. In some embodiments, the dipeptide spacer is selected from thegroup consisting of: Ala-Ala, β-Ala-β-Ala, Leu-Leu, Pro-Pro,γ-aminobutyric acid-γ-aminobutyric acid, Glu-Glu, and γ-Glu-γ-Glu.

Suitable methods of peptide acylation via amines, hydroxyls, and thiolsare known in the art. See, for example, Miller, Biochem Biophys ResCommun 218: 377-382 (1996); Shimohigashi and Stammer, Int J Pept ProteinRes 19: 54-62 (1982); and Previero et al., Biochim Biophys Acta 263:7-13 (1972) (for methods of acylating through a hydroxyl); and San andSilvius, J Pept Res 66: 169-180 (2005) (for methods of acylating througha thiol); Bioconjugate Chem. “Chemical Modifications of Proteins:History and Applications” pages 1, 2-12 (1990); Hashimoto et al.,Pharmaceutical Res. “Synthesis of Palmitoyl Derivatives of Insulin andtheir Biological Activity” Vol. 6, No: 2 pp. 171-176 (1989). The acylgroup of the acylated amino acid can be of any size, e.g., any lengthcarbon chain, and can be linear or branched. In some specificembodiments, the acyl group is a C₄ to C₃₀ fatty acid. For example, theacyl group can be any of a C₄ fatty acid, C₆ fatty acid, C₈ fatty acid,C₁₀ fatty acid, C₁₂ fatty acid, C₁₄ fatty acid, C₁₆ fatty acid, C₁₈fatty acid, C₂₀ fatty acid, C₂₂ fatty acid, C₂₄ fatty acid, C₂₆ fattyacid, C₂₈ fatty acid, or a C₃₀ fatty acid. In some embodiments, the acylgroup is a C₈ to C₂₀ fatty acid, e.g., a C₁₄ fatty acid or a C₁₆ fattyacid. In an alternative embodiment, the acyl group is a bile acid. Thebile acid can be any suitable bile acid, including, but not limited to,cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid,taurocholic acid, glycocholic acid, and cholesterol acid. In someembodiments, the peptide comprises an acylated amino acid by acylationof a long chain alkane on the peptide. In specific aspects, the longchain alkane comprises an amine, hydroxyl, or thiol group (e.g.,octadecylamine, tetradecanol, and hexadecanethiol) which reacts with acarboxyl group, or activated form thereof, of the peptide. The carboxylgroup, or activated form thereof, of the peptide can be part of a sidechain of an amino acid (e.g., glutamic acid, aspartic acid) of thepeptide or can be part of the analog backbone. In certain embodiments,the peptide is modified to comprise an acyl group by acylation of thelong chain alkane by a spacer which is attached to the peptide. Inspecific aspects, the long chain alkane comprises an amine, hydroxyl, orthiol group which reacts with a carboxyl group, or activated formthereof, of the spacer. Suitable spacers comprising a carboxyl group, oractivated form thereof, are described herein and include, for example,bifunctional spacers, e.g., amino acids, dipeptides, tripeptides,hydrophilic bifunctional spacers and hydrophobic bifunctional spacers.

As used herein, the term “activated form” of a carboxyl group refers toa carboxyl group with the general formula R(C═))X, wherein X is aleaving group and R is the peptide or the spacer. For example, activatedforms of a carboxyl groups may include, but are not limited to, acylchlorides, anhydrides, and esters. In some embodiments, the activatedcarboxyl group is an ester with a N-hydroxysuccinimide ester (NHS)leaving group.

With regard to these aspects, in which a long chain alkane is acylatedby the peptide or the spacer, the long chain alkane may be of any sizeand can comprise any length of carbon chain. The long chain alkane canbe linear or branched. In certain aspects, the long chain alkane is a C₄to C₃₀ alkane. For example, the long chain alkane can be any of a C₄alkane, C₆ alkane, C₈ alkane, C₁₀ alkane, C₁₂ alkane, C₁₄ alkane, C₁₆alkane, C₁₈ alkane, C₂₀ alkane, C₂₂ alkane, C₂₄ alkane, C₂₆ alkane, C₂₈alkane, or a C₃₀ alkane. In some embodiments, the long chain alkanecomprises a C₈ to C₂₀ alkane, e.g., a C₁₄ alkane, C₁₆ alkane, or a C₁₈alkane.

Also, in some embodiments, an amine, hydroxyl, or thiol group of thepeptide is acylated with a cholesterol acid. In a specific embodiment,the peptide is linked to the cholesterol acid through an alkylateddes-amino Cys spacer, i.e., an alkylated 3-mercaptopropionic acidspacer. The alkylated des-amino Cys spacer can be, for example, ades-amino-Cys spacer comprising a dodecaethylene glycol moiety. Forclarification, des-amino-Cys is 3-mercaptopropionic acid.

The peptides described herein can be further modified to comprise ahydrophilic moiety. In some specific embodiments the hydrophilic moietycan comprise a polyethylene glycol (PEG) chain. The incorporation of ahydrophilic moiety can be accomplished through any suitable means, suchas any of the methods described herein. In this regard, the peptide canof any of SEQ ID NOs: 1-213, 230-236 and 239, including any of themodifications described herein, in which at least one of the amino acidscomprises an acyl group and at least one of the amino acids iscovalently bonded to a hydrophilic moiety (e.g., PEG). In someembodiments, the acyl group is attached via a spacer comprising Cys,Lys, Orn, homo-Cys, or Ac-Phe, and the hydrophilic moiety isincorporated at a Cys residue.

Alternatively, the peptides can comprise a spacer, wherein the spacer isboth acylated and modified to comprise the hydrophilic moiety.Nonlimiting examples of suitable spacers include a spacer comprising oneor more amino acids selected from the group consisting of Cys, Lys, Orn,homo-Cys, and Ac-Phe.

In accordance with some embodiments, the peptide comprises an alkylatedamino acid (e.g., a non-coded alkylated amino acid (e.g., an amino acidcomprising an alkyl group which is non-native to a naturally-occurringamino acid)). Alkylation can be carried out at any positions within thepeptides, including any of the positions described herein as a site foracylation, including but not limited to, any of amino acid positions, ata position within a C-terminal extension, or at the C-terminus, providedthat the biological activity is retained. The alkyl group can becovalently linked directly to an amino acid of the peptides, orindirectly to an amino acid of the peptides via a spacer, wherein thespacer is positioned between the amino acid of the peptides and thealkyl group. The peptides may be alkylated at the same amino acidposition where a hydrophilic moiety is linked, or at a different aminoacid position. In specific aspects, the peptides are modified tocomprise an alkyl group by direct alkylation of an amine, hydroxyl, orthiol of a side chain of an amino acid of the peptides. In this regard,the alkylated peptides can comprise an amino acid sequence with at leastone of the amino acids modified to any amino acid comprising a sidechain amine, hydroxyl, or thiol. In yet other embodiments, the aminoacid comprising a side chain amine, hydroxyl, or thiol is adisubstituted amino acid. In some embodiments, the alkylated peptidecomprises a spacer between the peptide and the alkyl group. In someembodiments, the peptide is covalently bound to the spacer, which iscovalently bound to the alkyl group. In some exemplary embodiments, thepeptide is modified to comprise an alkyl group by alkylation of anamine, hydroxyl, or thiol of a spacer, which spacer is attached to aside chain of an amino acid. The amino acid to which the spacer isattached can be any amino acid comprising a moiety which permits linkageto the spacer. For example, an amino acid comprising a side chain NH₂,—OH, or —COOH (e.g., Lys, Orn, Ser, Asp, or Glu) is suitable. In someembodiments, the spacer is an amino acid comprising a side chain amine,hydroxyl, or thiol or a dipeptide or tripeptide comprising an amino acidcomprising a side chain amine, hydroxyl, or thiol. When alkylationoccurs through an amine group of a spacer, the alkylation can occurthrough the alpha amine of an amino acid or a side chain amine. In theinstance in which the alpha amine is alkylated, the amino acid of thespacer can be any amino acid. For example, the amino acid of the spacercan be a hydrophobic amino acid, e.g., Gly, Ala, Val, Leu, Ile, Trp,Met, Phe, Tyr, 6-amino hexanoic acid, 5-aminovaleric acid,7-aminoheptanoic acid, and 8-aminooctanoic acid. Alternatively, theamino acid of the spacer can be an acidic residue, e.g., Asp and Glu,provided that the alkylation occurs on the alpha amine of the acidicresidue. In the instance in which the side chain amine of the amino acidof the spacer is alkylated, the amino acid of the spacer is an aminoacid comprising a side chain amine, e.g., an amino acid of Formula I-III(e.g., Lys or Orn). In this instance, it is possible for both the alphaamine and the side chain amine of the amino acid of the spacer to bealkylated, such that the peptide is dialkylated. Embodiments of theinvention include such dialkylated molecules. When alkylation occursthrough a hydroxyl group of a spacer, the amino acid can be Ser. Whenalkylation occurs through a thiol group of spacer, the amino acid can beCys. In some embodiments, the spacer is a hydrophilic bifunctionalspacer. Suitable methods of peptide alkylation via amines, hydroxyls,and thiols are known in the art. For example, a Williamson ethersynthesis can be used to form an ether linkage between a hydroxyl groupof the peptides and the alkyl group. Also, a nucleophilic substitutionreaction of the peptide with an alkyl halide can result in any of anether, thioether, or amino linkage. The alkyl group of the alkylatedpeptides can be of any size, e.g., any length carbon chain, and can belinear or branched. In some embodiments, the alkyl group is a C₄ to C₃₀alkyl. For example, the alkyl group can be any of a C₄ alkyl, C₆ alkyl,C₈ alkyl, C₁₀ alkyl, C₁₂ alkyl, C₁₄ alkyl, C₁₆ alkyl, C₁₈ alkyl, C₂₀alkyl, C₂₂ alkyl, C₂₄ alkyl, C₂₆ alkyl, C₂₈ alkyl, or a C₃₀ alkyl. Insome embodiments, the alkyl group is a C₈ to C₂₀ alkyl, e.g., a C₁₄alkyl or a C₁₆ alkyl. In some embodiments of the disclosure, the peptidecomprises an alkylated amino acid by reacting a nucleophilic, long chainalkane with the peptide, wherein the peptide comprises a leaving groupsuitable for nucleophilic substitution. In specific aspects, thenucleophilic group of the long chain alkane comprises an amine,hydroxyl, or thiol group (e.g., octadecylamine, tetradecanol, andhexadecanethiol). The leaving group of the peptide can be part of a sidechain of an amino acid or can be part of the peptide backbone. Suitableleaving groups include, for example, N-hydroxysuccinimide, halogens, andsulfonate esters. In certain embodiments, the peptide is modified tocomprise an alkyl group by reacting the nucleophilic, long chain alkanewith a spacer which is attached to the peptide, wherein the spacercomprises the leaving group. In specific aspects, the long chain alkanecomprises an amine, hydroxyl, or thiol group. In certain embodiments,the spacer comprising the leaving group can be any spacer discussedherein, e.g., amino acids, dipeptides, tripeptides, hydrophilicbifunctional spacers and hydrophobic bifunctional spacers furthercomprising a suitable leaving group. With regard to these aspects of thedisclosure, in which a long chain alkane is alkylated by the peptides orthe spacer, the long chain alkane may be of any size and can compriseany length of carbon chain. The long chain alkane can be linear orbranched. In certain aspects, the long chain alkane is a C₄ to C₃₀alkane. For example, the long chain alkane can be any of a C₄ alkane, C₆alkane, C₈ alkane, C₁₀ alkane, C₁₂ alkane, C₁₄ alkane, C₁₆ alkane, C₁₈alkane, C₂₀ alkane, C₂₂ alkane, C₂₄ alkane, C₂₆ alkane, C₂₈ alkane, or aC₃₀ alkane. In some embodiments, the long chain alkane comprises a C₈ toC₂₀ alkane, e.g., a C₁₄ alkane, C₁₆ alkane, or a C₁₈ alkane. Also, insome embodiments, alkylation can occur between the peptides and acholesterol moiety. For example, the hydroxyl group of cholesterol candisplace a leaving group on the long chain alkane to form acholesterol-peptides product. The alkylated peptides described hereincan be further modified to comprise a hydrophilic moiety. In somespecific embodiments the hydrophilic moiety can comprise a polyethyleneglycol (PEG) chain. The incorporation of a hydrophilic moiety can beaccomplished through any suitable means, such as any of the methodsdescribed herein. Alternatively, the alkylated peptides can comprise aspacer, wherein the spacer is both alkylated and modified to comprisethe hydrophilic moiety. Nonlimiting examples of suitable spacers includea spacer comprising one or more amino acids selected from the groupconsisting of Cys, Lys, Orn, homo-Cys, and Ac-Phe.

In some embodiments, the peptide comprises at position 1 or 2, or atboth positions 1 and 2, an amino acid which achieves resistance of thepeptides to peptidase cleavage. In some embodiments, the peptidecomprises at position 1 an amino acid selected from the group consistingof: D-histidine, desaminohistidine, hydroxyl-histidine,acetyl-histidine, homo-histidine, N-methyl histidine, alpha-methylhistidine, imidazole acetic acid, or alpha, alpha-dimethyl imidiazoleacetic acid (DMIA). In some embodiments, the peptide comprises atposition 2 an amino acid selected from the group consisting of:D-serine, D-alanine, valine, glycine, N-methyl serine, N-methyl alanine,or alpha, aminoisobutyric acid. In some embodiments, the peptidecomprises at position 2 an amino acid which achieves resistance of thepeptide to peptidases and the amino acid which achieves resistance ofthe peptide to peptidases is not D-serine. In some embodiments, thiscovalent bond is an intramolecular bridge other than a lactam bridge.For example, suitable covalent bonding methods include any one or moreof olefin metathesis, lanthionine-based cyclization, disulfide bridge ormodified sulfur-containing bridge formation, the use ofα,ω-diaminoalkane tethers, the formation of metal-atom bridges, andother means of peptide cyclization.

In some embodiments, the peptide is modified by amino acid substitutionsand/or additions that introduce a charged amino acid into the C-terminalportion of the analog. In some embodiments, such modifications enhancestability and solubility. As used herein the term “charged amino acid”or “charged residue” refers to an amino acid that comprises a side chainthat is negative-charged (i.e., de-protonated) or positive-charged(i.e., protonated) in aqueous solution at physiological pH. In someaspects, these amino acid substitutions and/or additions that introducea charged amino acid modifications are at a C-terminal position. In someembodiments, one, two or three (and in some instances, more than three)charged amino acids are introduced at the C-terminal position. Inexemplary embodiments, one, two or all of the charged amino acids arenegative-charged. The negative-charged amino acid in some embodiments isaspartic acid, glutamic acid, cysteic acid, homocysteic acid, orhomoglutamic acid. In some aspects, these modifications increasesolubility.

In accordance with some embodiments, the peptides disclosed herein aremodified by truncation of the C-terminus by one or two amino acidresidues. In this regard, the peptides can comprise the sequences (SEQID NO: 1-213, 230-236 and 239), optionally with any of the additionalmodifications described herein.

In some embodiments, the peptide comprises a modified SEQ ID NO: 1-213,230-236 and 239 in which the carboxylic acid of the C-terminal aminoacid is replaced with a charge-neutral group, such as an amide or ester.Accordingly, in some embodiments, the peptide is an amidated peptide,such that the C-terminal residue comprises an amide in place of thealpha carboxylate of an amino acid. As used herein a general referenceto a peptide or analog is intended to encompass peptides that have amodified amino terminus, carboxy terminus, or both amino and carboxytermini. For example, an amino acid chain composing an amide group inplace of the terminal carboxylic acid is intended to be encompassed byan amino acid sequence designating the standard amino acids.

The invention further provides conjugates comprising one or more of thepeptides described herein conjugated to a heterologous moiety. As usedherein, the term “heterologous moiety” is synonymous with the term“conjugate moiety” and refers to any molecule (chemical or biochemical,naturally-occurring or non-coded) which is different from the peptidesdescribed herein. Exemplary conjugate moieties that can be linked to anyof the analogs described herein include but are not limited to aheterologous peptide or polypeptide (including for example, a plasmaprotein), a targeting agent, an immunoglobulin or portion thereof (e.g.,variable region, CDR, or Fc region), a diagnostic label such as aradioisotope, fluorophore or enzymatic label, a polymer including watersoluble polymers, or other therapeutic or diagnostic agents. In someembodiments a conjugate is provided comprising a peptide of the presentinvention and a plasma protein, wherein the plasma protein is selectedfrom the group consisting of albumin, transferin, fibrinogen andglobulins. In some embodiments the plasma protein moiety of theconjugate is albumin or transferin. The conjugate in some embodimentscomprises one or more of the peptides described herein and one or moreof: a different peptide (which is distinct from the peptides describedherein), a polypeptide, a nucleic acid molecule, an antibody or fragmentthereof, a polymer, a quantum dot, a small molecule, a toxin, adiagnostic agent, a carbohydrate, an amino acid. In some embodiments,the heterologous moiety is a polymer. In some embodiments, the polymeris selected from the group consisting of: polyamides, polycarbonates,polyalkylenes and derivatives thereof including, polyalkylene glycols,polyalkylene oxides, polyalkylene terepthalates, polymers of acrylic andmethacrylic esters, including poly(methyl methacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate), polyvinyl polymers including polyvinyl alcohols, polyvinylethers, polyvinyl esters, polyvinyl halides, poly(vinyl acetate), andpolyvinylpyrrolidone, polyglycolides, polysiloxanes, polyurethanes andco-polymers thereof, celluloses including alkyl cellulose, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitro celluloses, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propylmethyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate,cellulose propionate, cellulose acetate butyrate, cellulose acetatephthalate, carboxylethyl cellulose, cellulose triacetate, and cellulosesulphate sodium salt, polypropylene, polyethylenes includingpoly(ethylene glycol), poly(ethylene oxide), and poly(ethyleneterephthalate), and polystyrene. In some aspects, the polymer is abiodegradable polymer, including a synthetic biodegradable polymer(e.g., polymers of lactic acid and glycolic acid, polyanhydrides,poly(ortho)esters, polyurethanes, poly(butic acid), poly(valeric acid),and poly(lactide-cocaprolactone)), and a natural biodegradable polymer(e.g., alginate and other polysaccharides including dextran andcellulose, collagen, chemical derivatives thereof (substitutions,additions of chemical groups, for example, alkyl, alkylene,hydroxylations, oxidations, and other modifications routinely made bythose skilled in the art), albumin and other hydrophilic proteins (e.g.,zein and other prolamines and hydrophobic proteins)), as well as anycopolymer or mixture thereof. In general, these materials degrade eitherby enzymatic hydrolysis or exposure to water in vivo, by surface or bulkerosion. In some aspects, the polymer is a bioadhesive polymer, such asa bioerodible hydrogel described by H. S. Sawhney, C. P. Pathak and J.A. Hubbell in Macromolecules, 1993, 26, 581-587, the teachings of whichare incorporated herein, polyhyaluronic acids, casein, gelatin, glutin,polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methylmethacrylates), poly(ethyl methacrylates), poly(butylmethacrylate),poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), and poly(octadecyl acrylate). In some embodiments, thepolymer is a water-soluble polymer or a hydrophilic polymer. Hydrophilicpolymers are further described herein under “Hydrophilic Moieties.”Suitable water-soluble polymers are known in the art and include, forexample, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC; Klucel),hydroxypropyl methylcellulose (HPMC; Methocel), nitrocellulose,hydroxypropyl ethylcellulose, hydroxypropyl butylcellulose,hydroxypropyl pentylcellulose, methyl cellulose, ethylcellulose(Ethocel), hydroxyethyl cellulose, various alkyl celluloses andhydroxyalkyl celluloses, various cellulose ethers, cellulose acetate,carboxymethyl cellulose, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, vinyl acetate/crotonic acid copolymers,poly-hydroxyalkyl methacrylate, hydroxymethyl methacrylate, methacrylicacid copolymers, polymethacrylic acid, polymethylmethacrylate, maleicanhydride/methyl vinyl ether copolymers, poly vinyl alcohol, sodium andcalcium polyacrylic acid, polyacrylic acid, acidic carboxy polymers,carboxypolymethylene, carboxyvinyl polymers, polyoxyethylenepolyoxypropylene copolymer, polymethylvinylether co-maleic anhydride,carboxymethylamide, potassium methacrylate divinylbenzene co-polymer,polyoxyethyleneglycols, polyethylene oxide, and derivatives, salts, andcombinations thereof. In specific embodiments, the polymer is apolyalkylene glycol, including, for example, polyethylene glycol (PEG).In some embodiments, the heterologous moiety is a carbohydrate. In someembodiments, the carbohydrate is a monosaccharide (e.g., glucose,galactose, fructose), a disaccharide (e.g., sucrose, lactose, maltose),an oligosaccharide (e.g., raffinose, stachyose), a polysaccharide (astarch, amylase, amylopectin, cellulose, chitin, callose, laminarin,xylan, mannan, fucoidan, galactomannan. In some embodiments, theheterologous moiety is a lipid. The lipid, in some embodiments, is afatty acid, eicosanoid, prostaglandin, leukotriene, thromboxane, N-acylethanolamine), glycerolipid (e.g., mono-, di-, tri-substitutedglycerols), glycerophospholipid (e.g., phosphatidylcholine,phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine),sphingolipid (e.g., sphingosine, ceramide), sterol lipid (e.g., steroid,cholesterol), prenol lipid, saccharolipid, or a polyketide, oil, wax,cholesterol, sterol, fat-soluble vitamin, monoglyceride, diglyceride,triglyceride, a phospholipid. In some embodiments, the heterologousmoiety is attached via non-covalent or covalent bonding to the peptideof the present disclosure. In certain aspects, the heterologous moietyis attached to the peptide of the present disclosure via a linker.Linkage can be accomplished by covalent chemical bonds, physical forcessuch electrostatic, hydrogen, ionic, van der Waals, or hydrophobic orhydrophilic interactions. A variety of non-covalent coupling systems maybe used, including biotin-avidin, ligand/receptor, enzyme/substrate,nucleic acid/nucleic acid binding protein, lipid/lipid binding protein,cellular adhesion molecule partners; or any binding partners orfragments thereof which have affinity for each other. The peptide insome embodiments is linked to conjugate moieties via direct covalentlinkage by reacting targeted amino acid residues of the analog with anorganic derivatizing agent that is capable of reacting with selectedside chains or the N- or C-terminal residues of these targeted aminoacids. Reactive groups on the analog or conjugate moiety include, e.g.,an aldehyde, amino, ester, thiol, α-haloacetyl, maleimido or hydrazinogroup. Derivatizing agents include, for example, maleimidobenzoylsulfosuccinimide ester (conjugation through cysteine residues),N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinicanhydride or other agents known in the art. Alternatively, the conjugatemoieties can be linked to the analog indirectly through intermediatecarriers, such as polysaccharide or polypeptide carriers. Examples ofpolysaccharide carriers include aminodextran. Examples of suitablepolypeptide carriers include polylysine, polyglutamic acid, polyasparticacid, co-polymers thereof, and mixed polymers of these amino acids andothers, e.g., serines, to confer desirable solubility properties on theresultant loaded carrier. Cysteinyl residues are most commonly reactedwith α-haloacetates (and corresponding amines), such as chloroaceticacid, chloroacetamide to give carboxymethyl or carboxyamidomethylderivatives. Cysteinyl residues also are derivatized by reaction withbromotrifluoroacetone, alpha-bromo-β-(5-imidozoyl)propionic acid,chloroacetyl phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide,methyl 2-pyridyl disulfide, p-chloromercuribenzoate,2-chloromercuri-4-nitrophenol, or chloro-7-nitrobenzo-2-oxa-1,3-diazole.Histidyl residues are derivatized by reaction with diethylpyrocarbonateat pH 5.5-7.0 because this agent is relatively specific for the histidylside chain. Para-bromophenacyl bromide also is useful; the reaction ispreferably performed in 0.1 M sodium cacodylate at pH 6.0. Lysinyl andamino-terminal residues are reacted with succinic or other carboxylicacid anhydrides. Derivatization with these agents has the effect ofreversing the charge of the lysinyl residues. Other suitable reagentsfor derivatizing alpha-amino-containing residues include imidoesterssuch as methyl picolinimidate, pyridoxal phosphate, pyridoxal,chloroborohydride, trinitrobenzenesulfonic acid, O-methylisourea,2,4-pentanedione, and transaminase-catalyzed reaction with glyoxylate.Arginyl residues are modified by reaction with one or severalconventional reagents, among them phenylglyoxal, 2,3-butanedione,1,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residuesrequires that the reaction be performed in alkaline conditions becauseof the high pKa of the guanidine functional group. Furthermore, thesereagents may react with the groups of lysine as well as the arginineepsilon-amino group. The specific modification of tyrosyl residues maybe made, with particular interest in introducing spectral labels intotyrosyl residues by reaction with aromatic diazonium compounds ortetranitromethane. Most commonly, N-acetylimidizole andtetranitromethane are used to form O-acetyl tyrosyl species and 3-nitroderivatives, respectively. Carboxyl side groups (aspartyl or glutamyl)are selectively modified by reaction with carbodiimides (R—N═N—R′),where R and R′ are different alkyl groups, such as1-cyclohexyl-3-(2-morpholinyl-4-ethyl) carbodiimide or1-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide. Furthermore,aspartyl and glutamyl residues are converted to asparaginyl andglutaminyl residues by reaction with ammonium ions. Other modificationsinclude hydroxylation of proline and lysine, phosphorylation of hydroxylgroups of seryl or threonyl residues, methylation of the alpha-aminogroups of lysine, arginine, and histidine side chains (T. E. Creighton,Proteins: Structure and Molecular Properties, W.H. Freeman & Co., SanFrancisco, pp. 79-86 (1983)), deamidation of asparagine or glutamine,acetylation of the N-terminal amine, and/or amidation or esterificationof the C-terminal carboxylic acid group. Another type of covalentmodification involves chemically or enzymatically coupling glycosides tothe peptide. Sugar(s) may be attached to (a) arginine and histidine, (b)free carboxyl groups, (c) free sulfhydryl groups such as those ofcysteine, (d) free hydroxyl groups such as those of serine, threonine,or hydroxyproline, (e) aromatic residues such as those of tyrosine, ortryptophan, or (f) the amide group of glutamine. These methods aredescribed in WO87/05330 published 11 Sep. 1987, and in Aplin andWriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981). In someembodiments, the peptide is conjugated to a heterologous moiety viacovalent linkage between a side chain of an amino acid of the peptidesand the heterologous moiety. In some aspects, the amino acid covalentlylinked to a heterologous moiety (e.g., the amino acid comprising aheterologous moiety) is a Cys, Lys, Orn, homo-Cys, or Ac-Phe, and theside chain of the amino acid is covalently bonded to a heterologousmoiety. In some embodiments, the conjugate comprises a linker that joinsthe peptide to the heterologous moiety. In some aspects, the linkercomprises a chain of atoms from 1 to about 60, or 1 to 30 atoms orlonger, 2 to 5 atoms, 2 to 10 atoms, 5 to 10 atoms, or 10 to 20 atomslong. In some embodiments, the chain atoms are all carbon atoms. In someembodiments, the chain atoms in the backbone of the linker are selectedfrom the group consisting of C, O, N, and S. Chain atoms and linkers maybe selected according to their expected solubility (hydrophilicity) soas to provide a more soluble conjugate. In some embodiments, the linkerprovides a functional group that is subject to cleavage by an enzyme orother catalyst or hydrolytic conditions found in the target tissue ororgan or cell. In some embodiments, the length of the linker is longenough to reduce the potential for steric hindrance. If the linker is acovalent bond or a peptidyl bond and the conjugate is a polypeptide, theentire conjugate can be a fusion protein. Such peptidyl linkers may beany length. Exemplary linkers are from about 1 to 50 amino acids inlength, 5 to 50, 3 to 5, 5 to 10, 5 to 15, or 10 to 30 amino acids inlength. Such fusion proteins may alternatively be produced byrecombinant genetic engineering methods known to one of ordinary skillin the art. As noted above, in some embodiments, the peptides areconjugated, e.g., fused to an immunoglobulin or portion thereof (e.g.,variable region, CDR, or Fc region). Known types of immunoglobulins (Ig)include IgG, IgA, IgE, IgD or IgM. The Fc region is a C-terminal regionof an Ig heavy chain, which is responsible for binding to Fc receptorsthat carry out activities such as recycling (which results in prolongedhalf-life), antibody dependent cell-mediated cytotoxicity (ADCC), andcomplement dependent cytotoxicity (CDC). For example, according to somedefinitions the human IgG heavy chain Fc region stretches from Cys226 tothe C-terminus of the heavy chain. The “hinge region” generally extendsfrom Glu216 to Pro230 of human IgG1 (hinge regions of other IgG isotypesmay be aligned with the IgG1 sequence by aligning the cysteines involvedin cysteine bonding). The Fc region of an IgG includes two constantdomains, CH2 and CH3. The CH2 domain of a human IgG Fc region usuallyextends from amino acids 231 to amino acid 341. The CH3 domain of ahuman IgG Fc region usually extends from amino acids 342 to 447.References made to amino acid numbering of immunoglobulins orimmunoglobulin fragments, or regions, are all based on Kabat et al.1991, Sequences of Proteins of Immunological Interest, U.S. Departmentof Public Health, Bethesda, Md. In related embodiments, the Fc regionmay comprise one or more native or modified constant regions from animmunoglobulin heavy chain, other than CH1, for example, the CH2 and CH3regions of IgG and IgA, or the CH3 and CH4 regions of IgE. Suitableconjugate moieties include portions of immunoglobulin sequence thatinclude the FcRn binding site. FcRn, a salvage receptor, is responsiblefor recycling immunoglobulins and returning them to circulation inblood. The region of the Fc portion of IgG that binds to the FcRnreceptor has been described based on X-ray crystallography (Burmeisteret al. 1994, Nature 372:379). The major contact area of the Fc with theFcRn is near the junction of the CH2 and CH3 domains. Fc-FcRn contactsare all within a single Ig heavy chain. The major contact sites includeamino acid residues 248, 250-257, 272, 285, 288, 290-291, 308-311, and314 of the CH2 domain and amino acid residues 385-387, 428, and 433-436of the CH3 domain. Some conjugate moieties may or may not include FcγRbinding site(s). FcγR are responsible for ADCC and CDC. Examples ofpositions within the Fc region that make a direct contact with FcγR areamino acids 234-239 (lower hinge region), amino acids 265-269 (B/Cloop), amino acids 297-299 (C′/E loop), and amino acids 327-332 (F/G)loop (Sondermann et al., Nature 406: 267-273, 2000). The lower hingeregion of IgE has also been implicated in the FcRI binding (Henry, etal., Biochemistry 36, 15568-15578, 1997). Residues involved in IgAreceptor binding are described in Lewis et al., (J Immunol.175:6694-701, 2005). Amino acid residues involved in IgE receptorbinding are described in Sayers et al. (J Biol Chem. 279(34):35320-5,2004). Amino acid modifications may be made to the Fc region of animmunoglobulin. Such variant Fc regions comprise at least one amino acidmodification in the CH3 domain of the Fc region (residues 342-447)and/or at least one amino acid modification in the CH2 domain of the Fcregion (residues 231-341). Mutations believed to impart an increasedaffinity for FcRn include T256A, T307A, E380A, and N434A (Shields et al.2001, J. Biol. Chem. 276:6591). Other mutations may reduce binding ofthe Fc region to FcγRI, FcγRIIA, FcγRIIB, and/or FcγRIIIA withoutsignificantly reducing affinity for FcRn. For example, substitution ofthe Asn at position 297 of the Fc region with Ala or another amino acidremoves a highly conserved N-glycosylation site and may result inreduced immunogenicity with concomitant prolonged half-life of the Fcregion, as well as reduced binding to FcγRs (Routledge et al. 1995,Transplantation 60:847; Friend et al. 1999, Transplantation 68:1632;Shields et al. 1995, J. Biol. Chem. 276:6591). Amino acid modificationsat positions 233-236 of IgG have been made that reduce binding to FcγRs(Ward and Ghetie 1995, Therapeutic Immunology 2:77 and Armour et al.1999, Eur. J. Immunol. 29:2613). Some exemplary amino acid substitutionsare described in U.S. Pat. Nos. 7,355,008 and 7,381,408, eachincorporated by reference herein in its entirety. The peptides describedherein can be further modified to improve its solubility and stabilityin aqueous solutions at physiological pH, while retaining the biologicalactivity. Hydrophilic moieties such as PEG groups can be attached to theanalogs under any suitable conditions used to react a protein with anactivated polymer molecule. Any means known in the art can be used,including via acylation, reductive alkylation, Michael addition, thiolalkylation or other chemoselective conjugation/ligation methods througha reactive group on the PEG moiety (e.g., an aldehyde, amino, ester,thiol, α-haloacetyl, maleimido or hydrazino group) to a reactive groupon the target compound (e.g., an aldehyde, amino, ester, thiol,α-haloacetyl, maleimido or hydrazino group). Activating groups which canbe used to link the water soluble polymer to one or more proteinsinclude without limitation sulfone, maleimide, sulfhydryl, thiol,triflate, tresylate, azidirine, oxirane, 5-pyridyl, andalpha-halogenated acyl group (e.g., alpha-iodo acetic acid,alpha-bromoacetic acid, alpha-chloroacetic acid). If attached to theanalog by reductive alkylation, the polymer selected should have asingle reactive aldehyde so that the degree of polymerization iscontrolled. See, for example, Kinstler et al., Adv. Drug. Delivery Rev.54: 477-485 (2002); Roberts et al., Adv. Drug Delivery Rev. 54: 459-476(2002); and Zalipsky et al., Adv. Drug Delivery Rev. 16: 157-182 (1995).In specific aspects, an amino acid residue of the peptides having athiol is modified with a hydrophilic moiety such as PEG. In someembodiments, the thiol is modified with maleimide-activated PEG in aMichael addition reaction to result in a PEGylated analog comprising athioether linkage. In some embodiments, the thiol is modified with ahaloacetyl-activated PEG in a nucleophilic substitution reaction toresult in a PEGylated analog comprising a thioether linkage. Suitablehydrophilic moieties include polyethylene glycol (PEG), polypropyleneglycol, polyoxyethylated polyols (e.g., POG), polyoxyethylated sorbitol,polyoxyethylated glucose, polyoxyethylated glycerol (POG),polyoxyalkylenes, polyethylene glycol propionaldehyde, copolymers ofethylene glycol/propylene glycol, monomethoxy-polyethylene glycol,mono-(C1-C10) alkoxy- or aryloxy-polyethylene glycol,carboxymethylcellulose, polyacetals, polyvinyl alcohol (PVA), polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleicanhydride copolymer, poly (.beta.-amino acids) (either homopolymers orrandom copolymers), poly(n-vinyl pyrrolidone)polyethylene glycol,propropylene glycol homopolymers (PPG) and other polyakylene oxides,polypropylene oxide/ethylene oxide copolymers, colonic acids or otherpolysaccharide polymers, Ficoll or dextran and mixtures thereof.Dextrans are polysaccharide polymers of glucose subunits, predominantlylinked by α1-6 linkages. Dextran is available in many molecular weightranges, e.g., about 1 kD to about 100 kD, or from about 5, 10, 15 or 20kD to about 20, 30, 40, 50, 60, 70, 80 or 90 kD. Linear or branchedpolymers are contemplated. Resulting preparations of conjugates may beessentially monodisperse or polydisperse, and may have about 0.5, 0.7,1, 1.2, 1.5 or 2 polymer moieties per analog. In some embodiments, thepeptide is conjugated to a hydrophilic moiety via covalent linkagebetween a side chain of an amino acid of the peptide and the hydrophilicmoiety. In some embodiments, the peptide is conjugated to a hydrophilicmoiety via the side chain of an amino acid, a position within aC-terminal extension, or the C-terminal amino acid, or a combination ofthese positions. In some aspects, the amino acid covalently linked to ahydrophilic moiety (e.g., the amino acid comprising a hydrophilicmoiety) is a Cys, Lys, Orn, homo-Cys, or Ac-Phe, and the side chain ofthe amino acid is covalently bonded to a hydrophilic moiety (e.g., PEG).In some embodiments, the conjugate of the present disclosure comprisesthe peptide fused to an accessory analog which is capable of forming anextended conformation similar to chemical PEG (e.g., a recombinant PEG(rPEG) molecule), such as those described in International PatentApplication Publication No. WO2009/023270 and U.S. Patent ApplicationPublication No. US20080286808. The rPEG molecule in some aspects is apolypeptide comprising one or more of glycine, serine, glutamic acid,aspartic acid, alanine, or proline. In some aspects, the rPEG is ahomopolymer, e.g., poly-glycine, poly-serine, poly-glutamic acid,poly-aspartic acid, poly-alanine, or poly-proline. In other embodiments,the rPEG comprises two types of amino acids repeated, e.g.,poly(Gly-Ser), poly(Gly-Glu), poly(Gly-Ala), poly(Gly-Asp),poly(Gly-Pro), poly(Ser-Glu), etc. In some aspects, the rPEG comprisesthree different types of amino acids, e.g., poly(Gly-Ser-Glu). Inspecific aspects, the rPEG increases the half-life of the peptide. Insome aspects, the rPEG comprises a net positive or net negative charge.The rPEG in some aspects lacks secondary structure. In some embodiments,the rPEG is greater than or equal to 10 amino acids in length and insome embodiments is about 40 to about 50 amino acids in length. Theaccessory peptide in some aspects is fused to the N- or C-terminus ofthe peptide of the present disclosure through a peptide bond or aproteinase cleavage site, or is inserted into the loops of the peptideof the present disclosure. The rPEG in some aspects comprises anaffinity tag or is linked to a PEG that is greater than 5 kDa. In someembodiments, the rPEG confers the peptide of the present disclosure withan increased hydrodynamic radius, serum half-life, protease resistance,or solubility and in some aspects confers the analog with decreasedimmunogenicity.

The invention further provides multimers or dimers of the peptidesdisclosed herein, including homo- or hetero-multimers or homo- orhetero-dimers. Two or more of the analogs can be linked together usingstandard linking agents and procedures known to those skilled in theart. For example, dimers can be formed between two peptides through theuse of bifunctional thiol crosslinkers and bi-functional aminecrosslinkers, particularly for the analogs that have been substitutedwith cysteine, lysine ornithine, homocysteine or acetyl phenylalanineresidues. The dimer can be a homodimer or alternatively can be aheterodimer. In certain embodiments, the linker connecting the two (ormore) analogs is PEG, e.g., a 5 kDa PEG, 20 kDa PEG. In someembodiments, the linker is a disulfide bond. For example, each monomerof the dimer may comprise a Cys residue (e.g., a terminal or internallypositioned Cys) and the sulfur atom of each Cys residue participates inthe formation of the disulfide bond. In some aspects, the monomers areconnected via terminal amino acids (e.g., N-terminal or C-terminal), viainternal amino acids, or via a terminal amino acid of at least onemonomer and an internal amino acid of at least one other monomer. Inspecific aspects, the monomers are not connected via an N-terminal aminoacid. In some aspects, the monomers of the multimer are attachedtogether in a “tail-to-tail” orientation in which the C-terminal aminoacids of each monomer are attached together.

Peptides of the invention are made in a variety of ways known in theart. Suitable methods of de novo synthesizing peptides are described in,for example, Merrifield, J. Am. Chem. Soc, 85, 2149 (1963); Davis etal., Biochem. Intl., 10, 394-414 (1985); Larsen et al., J. Am. Chem.Soc, 115, 6247 (1993); Smith et al., J. Peptide Protein Res., 44, 183(1994); O'Donnell et al., J. Am. Chem. Soc, 118, 6070 (1996); Stewartand Young, Solid Phase Peptide Synthesis, Freeman (1969); Finn et al.,The Proteins, 3 ed., vol. 2, pp. 105-253 (1976); Erickson et al., TheProteins, 3^(rd) ed., vol. 2, pp. 257-527 (1976); and Chan et al., FmocSolid Phase Peptide Synthesis, Oxford University Press, Oxford, UnitedKingdom, 2005. The invention contemplates synthetic peptides.

Alternatively, the peptide is expressed recombinantly by introducing anucleic acid encoding a peptide of the invention into host cells, whichare cultured to express the peptide using standard recombinant methods.Exemplary nucleic acids include deoxyribonucleic acid (DNA) andribonucleic acids (RNA). In some variations, the nucleic acid isintroduced in an expression vector. See, for instance, Sambrook et al.,Molecular Cloning: A Laboratory Manual. 3rd ed., Cold Spring HarborPress, Cold Spring Harbor, N.Y. 2001; and Ausubel et al., CurrentProtocols in Molecular Biology, Greene Publishing Associates and JohnWiley & Sons, N.Y., 1994. Such peptides are purified from the culturemedia or cell pellets.

In some embodiments, the peptides of the disclosure are isolated. Insome embodiments, the peptides of the disclosure are purified. It isrecognized that “purity” is a relative term, and not to be necessarilyconstrued as absolute purity or absolute enrichment or absoluteselection. In some aspects, the purity is at least or about 50%, is atleast or about 60%, at least or about 70%, at least or about 80%, or atleast or about 90% (e.g., at least or about 91%, at least or about 92%,at least or about 93%, at least or about 94%, at least or about 95%, atleast or about 96%, at least or about 97%, at least or about 98%, atleast or about 99% or is approximately 100%.

In some embodiments, the peptides described herein are commerciallysynthesized by companies, such as Innopep Inc. (San Diego, Calif.). Inthis respect, the peptides can be synthetic, recombinant, isolated,and/or purified.

The peptides of the present disclosure can be provided in accordancewith one embodiment as part of a kit. Accordingly, in some embodiments,a kit for administering a peptide, to a patient in need thereof isprovided wherein the kit comprises a peptide as described herein.

In one embodiment the kit is provided with a device for administeringthe composition to a patient, e.g., syringe needle, pen device, jetinjector or other needle-free injector. The kit may alternatively or inaddition include one or more containers, e.g., vials, tubes, bottles,single or multi-chambered pre-filled syringes, cartridges, infusionpumps (external or implantable), jet injectors, pre-filled pen devicesand the like, optionally containing the peptide in a lyophilized form orin an aqueous solution. The kits in some embodiments compriseinstructions for use. In accordance with one embodiment the device ofthe kit is an aerosol dispensing device, wherein the composition isprepackaged within the aerosol device. In another embodiment the kitcomprises a syringe and a needle, and in one embodiment the sterilecomposition is prepackaged within the syringe.

A further embodiment of the invention includes a process of treatingcancer comprising

-   -   i. A] prescribing    -   ii. B] selling or advertising to sell,    -   iii. C] purchasing,    -   iv. D] instructing to self-administer, or    -   v. E] administering    -   of a compound described herein, wherein the compound has been        approved by a regulatory agency for the treatment of a        condition, to a subject in need of treatment.

A further embodiment of the invention includes a method of supplying apeptide for treating a disease, said method comprises reimbursing aphysician, a formulary, a patient or an insurance company for the saleof said peptide.

Definitions

The terms “peptide” refers to a molecule comprising two or more aminoacid residues joined to each other by peptide bonds. These termsencompass, e.g., native and artificial proteins, protein fragments andpolypeptide analogs (such as muteins, variants, and fusion proteins) ofa protein sequence as well as post-translationally, or otherwisecovalently or non-covalently, modified peptides. A peptide may bemonomeric or polymeric. In certain embodiments, “peptides” are chains ofamino acids whose alpha carbons are linked through peptide bonds. Theterminal amino acid at one end of the chain (amino terminal) thereforehas a free amino group, while the terminal amino acid at the other endof the chain (carboxy terminal) has a free carboxyl group. As usedherein, the term “amino terminus” (abbreviated N-terminus) refers to thefree α-amino group on an amino acid at the amino terminal of a peptideor to the α-amino group (imino group when participating in a peptidebond) of an amino acid at any other location within the peptide.Similarly, the term “carboxy terminus” refers to the free carboxyl groupon the carboxy terminus of a peptide or the carboxyl group of an aminoacid at any other location within the peptide. Peptides also includeessentially any polyamino acid including, but not limited to, peptidemimetics such as amino acids joined by an ether as opposed to an amidebond.

The term “therapeutic peptide” refers to peptides or fragments orvariants thereof, having one or more therapeutic and/or biologicalactivities.

The term “analog” as used herein describes a peptide comprising one ormore amino acid modifications, such as but not limited to substitutionand/or one or more deletion and/or one or more addition of any one ofthe amino acid residues for any natural or unnatural amino acid,synthetic amino acids or peptidomimetics and/or the attachment of a sidechain to any one of the natural or unnatural amino acids, syntheticamino acids or peptidomimetics at any available position. The additionor deletion of amino acid residues can take place at the N-terminal ofthe peptide and/or at the C-terminal of the peptide.

Peptide sequences are indicated using standard one- or three-letterabbreviations. Unless otherwise indicated, peptide sequences have theiramino termini at the left and their carboxy termini at the right. Aparticular section of a peptide can be designated by amino acid residuenumber such as amino acids 3 to 6, or by the actual residue at that sitesuch as Met3 to Gly6. A particular peptide sequence also can bedescribed by explaining how it differs from a reference sequence.

When used herein the term “natural amino acid” is an amino acid (withthe usual three letter codes & one letter codes in parenthesis) selectedfrom the group consisting of: Glycine (Gly & G), proline (Pro & P),alanine (Ala & A), valine (Val & V), leucine (Leu & L), isoleucine (Ile& I), methionine (Met & M), cysteine (Cys & C), phenylalanine (Phe & F),tyrosine (Tyr & Y), tryptophan (Trp & W), histidine (His & H), lysine(Lys & K), arginine (Arg & R), glutamine (Gln & Q), asparagine (Asn &N), glutamic acid (Glu & E), aspartic acid (Asp & D), serine (Ser & S)and threonine (Thr & T). If anywhere in this invention reference is madeto a peptide, analog or derivative or peptides according to thisinvention comprising or not comprising G, P, A, V, L, I, M, C, F, Y, H,K, R, Q, N, E, D, S or T, without specifying further, amino acids aremeant. If not otherwise indicated amino acids indicated with a singleletter code in CAPITAL letters indicate the L-isoform, if however theamino acid is indicated with a lower case letter, this amino acid isused/applied as it's D-form.

If, due to typing errors, there are deviations from the commonly usedcodes, the commonly used codes apply. The amino acids present in thepeptides of the present invention are, preferably, amino acids which canbe coded for by a nucleic acid. As is apparent from the above examples,amino acid residues may be identified by their full name, theirone-letter code, and/or their three-letter code. These three ways arefully equivalent.

A “non-conservative amino acid substitution” refers to the substitutionof a member of one of these classes for a member from another class. Inmaking such changes, according to certain embodiments, the hydropathicindex of amino acids may be considered. Each amino acid has beenassigned a hydropathic index on the basis of its hydrophobicity andcharge characteristics. They are: isoleucine (+4.5); valine (+4.2);leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5);methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7);serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (−1.6);histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5);asparagine (−3.5); lysine (−3.9); and arginine (−4.5). The importance ofthe hydropathic amino acid index in conferring interactive biologicalfunction on a protein is understood in the art (see, for example, Kyteet al., 1982, J. Mol. Biol. 157:105-131). It is known that certain aminoacids may be substituted for other amino acids having a similarhydropathic index or score and still retain a similar biologicalactivity. In making changes based upon the hydropathic index, in certainembodiments, the substitution of amino acids whose hydropathic indicesare within ±2 is included. In certain embodiments, those that are within±1 are included, and in certain embodiments, those within ±0.5 areincluded. It is also understood in the art that the substitution of likeamino acids can be made effectively on the basis of hydrophilicity,particularly where the biologically functional protein or peptidethereby created is intended for use in immunological embodiments, asdisclosed herein. In certain embodiments, the greatest local averagehydrophilicity of a protein, as governed by the hydrophilicity of itsadjacent amino acids, correlates with its immunogenicity andantigenicity, i.e., with a biological property of the protein. Thefollowing hydrophilicity values have been assigned to these amino acidresidues: arginine (+3.0); lysine (+3.0); aspartate (+3.0.+−. 1);glutamate (+3.0.+−0.1); serine (+0.3); asparagine (+0.2); glutamine(+0.2); glycine (0); threonine (−0.4); proline (−0.5.+−0.1); alanine(−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine(−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3);phenylalanine (−2.5) and tryptophan (−3.4). In making changes based uponsimilar hydrophilicity values, in certain embodiments, the substitutionof amino acids whose hydrophilicity values are within ±2 is included, incertain embodiments, those that are within ±1 are included, and incertain embodiments, those within ±0.5 are included.

Other exemplary amino acid substitutions are set forth in Table 3.

TABLE 3 Original Preferred Residues Substitutions Substitutions Ala Val,Leu, Ile Val Arg Lys, Gln, Asn Lys Asn Gln Asp Glu Cys Ser, Ala Ser GlnAsn Asn Glu Asp Asp Gly Pro, Ala Ala His Asn, Gln, Lys, Arg Arg Ile Leu,Val, Met, Ala, Phe, Nle Leu Leu Norleucine, Ile, Val, Met, Ala, Phe IleLys Arg, Gln, Asn, 1,4-Diamino-butyric Acid Arg Met Leu, Phe, Ile LeuPhe Leu, Val, Ile, Ala, Tyr Leu Pro Ala Gly Ser Thr, Ala, Cys Thr ThrSer Ser Trp Tyr, Phe Tyr Tyr Trp, Phe, Thr, Ser Phe Val Ile, Met, Leu,Phe, Ala, Nle Leu

As used herein the term “charged amino acid” or “charged residue” refersto an amino acid that comprises a side chain that is negative-charged(i.e., de-protonated) or positive-charged (i.e., protonated) in aqueoussolution at physiological pH. For example negative-charged amino acidsinclude aspartic acid, glutamic acid, cysteic acid, homocysteic acid,and homoglutamic acid, whereas positive-charged amino acids includearginine, lysine and histidine. Charged amino acids include the chargedamino acids among the 20 coded amino acids, as well as atypical ornon-naturally occurring or non-coded amino acids.

As used herein the term “acidic amino acid” refers to an amino acid thatcomprises a second acidic moiety (other than the carboxylic acid of theamino acid), including for example, a carboxylic acid or sulfonic acidgroup.

As used herein, the term “acylated amino acid” refers to an amino acidcomprising an acyl group which is non-native to a naturally-occurringamino acid, regardless of the means by which it is produced (e.g.acylation prior to incorporating the amino acid into a peptide, oracylation after incorporation into a peptide).

As used herein the term “alkylated amino acid” refers to an amino acidcomprising an alkyl group which is non-native to a naturally-occurringamino acid, regardless of the means by which it is produced.Accordingly, the acylated amino acids and alkylated amino acids of thepresent disclosures are non-coded amino acids.

A skilled artisan will be able to determine suitable variants ofpeptides as set forth herein using well-known techniques. In certainembodiments, one skilled in the art may identify suitable areas of themolecule that may be changed without destroying activity by targetingregions not believed to be important for activity. In other embodiments,the skilled artisan can identify residues and portions of the moleculesthat are conserved among similar peptides. In further embodiments, evenareas that may be important for biological activity or for structure maybe subject to conservative amino acid substitutions without destroyingthe biological activity or without adversely affecting the peptidestructure.

Additionally, one skilled in the art can review structure-functionstudies identifying residues in similar peptides that are important foractivity or structure. In view of such a comparison, the skilled artisancan predict the importance of amino acid residues in a peptide thatcorrespond to amino acid residues important for activity or structure insimilar peptides. One skilled in the art may opt for chemically similaramino acid substitutions for such predicted important amino acidresidues.

One skilled in the art can also analyze the three-dimensional structureand amino acid sequence in relation to that structure in similarpeptides. In view of such information, one skilled in the art maypredict the alignment of amino acid residues of a peptide with respectto its three-dimensional structure. In certain embodiments, one skilledin the art may choose to not make radical changes to amino acid residuespredicted to be on the surface of the peptide, since such residues maybe involved in important interactions with other molecules. Moreover,one skilled in the art may generate test variants containing a singleamino acid substitution at each desired amino acid residue. The variantscan then be screened using activity assays known to those skilled in theart. Such variants could be used to gather information about suitablevariants. For example, if one discovered that a change to a particularamino acid residue resulted in destroyed, undesirably reduced, orunsuitable activity, variants with such a change can be avoided. Inother words, based on information gathered from such routineexperiments, one skilled in the art can readily determine the aminoacids where further substitutions should be avoided either alone or incombination with other mutations.

The term “derivative” as used herein means a chemically modifiedpeptide, in which one or more side chains have been covalently attachedto the peptide. The term “side chain” may also be referred to as a“substituent”. A derivative comprising such side chains will thus be“derivatized” peptide or “derivatized” analog. The term may also referto peptides containing one or more chemical moieties not normally a partof the peptide molecule such as esters and amides of free carboxygroups, acyl and alkyl derivatives of free amino groups, phospho estersand ethers of free hydroxy groups. Such modifications may be introducedinto the molecule by reacting targeted amino acid residues of thepeptide with an organic derivatizing agent that is capable of reactingwith selected side chains or terminal residues. Preferred chemicalderivatives include peptides that have been phosphorylated, C-terminiamidated or N-termini acetylated. The term may also refer to peptides ofthe invention as used herein which may be prepared from the functionalgroups which occur as side chains on the residues or the N- orC-terminal groups, by means known in the art, and are included in theinvention as long as they remain pharmaceutically acceptable, i.e., theydo not destroy the activity of the peptide, do not confer toxicproperties on compositions containing it and do not adversely affect theantigenic properties thereof. These derivatives may, for example,include aliphatic esters of the carboxyl groups, amides of the carboxylgroups produced by reaction with ammonia or with primary or secondaryamines, N-acyl derivatives of free amino groups of the amino acidresidues formed by reaction with acyl moieties (e.g., alkanoyl orcarbocyclic aroyl groups) or O-acyl derivatives of free hydroxyl group(for example that of seryl or threonyl residues) formed by reaction withacyl moieties.

A modified amino acid residue is an amino acid residue in which anygroup or bond was modified by deletion, addition, or replacement with adifferent group or bond, as long as the functionality of the amino acidresidue is preserved or if functionality changed (for examplereplacement of tyrosine with substituted phenylalanine) as long as themodification did not impair the activity of the peptide containing themodified residue.

The term “substituent” or “side chain” as used herein means any suitablemoiety bonded, in particular covalently bonded, to an amino acidresidue, in particular to any available position on an amino acidresidue. Typically, the suitable moiety is a chemical moiety.

The term “fatty acid” refers to aliphatic monocarboxylic acids havingfrom 4 to 28 carbon atoms, it is preferably un-branched, and it may besaturated or unsaturated. In the present invention fatty acidscomprising 10 to 16 amino acids are preferred.

The term “fatty diacid” refers to fatty acids as defined above but withan additional carboxylic acid group in the omega position. Thus, fattydiacids are dicarboxylic acids. In the present invention fatty acidscomprising 14 to 20 amino acids are preferred.

The term “% sequence identity” is used interchangeably herein with theterm “% identity” and refers to the level of amino acid sequenceidentity between two or more peptide sequences or the level ofnucleotide sequence identity between two or more nucleotide sequences,when aligned using a sequence alignment program. For example, as usedherein, 80% identity means the same thing as 80% sequence identitydetermined by a defined algorithm, and means that a given sequence is atleast 80% identical to another length of another sequence.

The term “% sequence homology” is used interchangeably herein with theterm “% homology” and refers to the level of amino acid sequencehomology between two or more peptide sequences or the level ofnucleotide sequence homology between two or more nucleotide sequences,when aligned using a sequence alignment program. For example, as usedherein, 80% homology means the same thing as 80% sequence homologydetermined by a defined algorithm, and accordingly a homolog of a givensequence has greater than 80% sequence homology over a length of thegiven sequence.

Exemplary computer programs which can be used to determine identitybetween two sequences include, but are not limited to, the suite ofBLAST programs, e.g., BLASTN, BLASTX, and TBLASTX, BLASTP and TBLASTN,publicly available on the Internet at the NCBI website. See alsoAltschul et al., 1990, J. Mol. Biol. 215:403-10 (with special referenceto the published default setting, i.e., parameters w=4, t=17) andAltschul et al., 1997, Nucleic Acids Res., 25:3389-3402. Sequencesearches are typically carried out using the BLASTP program whenevaluating a given amino acid sequence relative to amino acid sequencesin the GenBank Protein Sequences and other public databases. The BLASTXprogram is preferred for searching nucleic acid sequences that have beentranslated in all reading frames against amino acid sequences in theGenBank Protein Sequences and other public databases. Both BLASTP andBLASTX are run using default parameters of an open gap penalty of 11.0,and an extended gap penalty of 1.0, and utilize the BLOSUM-62 matrix.(Id). In addition to calculating percent sequence identity, the BLASTalgorithm also performs a statistical analysis of the similarity betweentwo sequences (see, e.g., Karlin & Altschul, Proc. Nat'l. Acad. Sci.USA, 90:5873-5787 (1993)). One measure of similarity provided by theBLAST algorithm is the smallest sum probability (P(N)), which providesan indication of the probability by which a match between two nucleotideor amino acid sequences would occur by chance.

The term “cells expressing the mutant p53 protein” as used herein refersto cells which express from at least one allele a mutant p53 protein. Incertain embodiments, the term “cells expressing the mutant p53 protein”is interchangeable with “cancer cells”.

The term “pro-apoptotic genes” refers to a gene, or a multitude ofgenes, involved in apoptosis, either directly (such as certain caspases)or indirectly (for example, as part of a signal transduction cascade).

The term “associated with a mutant p53 protein” as used herein refers toany disease, disorder or condition which is caused by a mutant p53protein or related to the presence of a mutant p53 protein in a cell oran organ.

It should be understood that since p53 is expressed from both alleles,the overall content of intra-cellular p53 can be either wild-type(wt/wt), mixture of wt and mutant p53 (wt/mut) or mutant p53 only (whenboth alleles are mutated (mut/mut), or one allele is deleted (mut/−)).In cancer, the situation is often wt/mut, mut/mut or mut/−. Since p53acts as a tetramer, mutant p53 proteins may abrogate the activity ofwild type p53 proteins, which do exist in the cancer's cells. Therefore,the peptides provided by the present invention are particularly usefulin treating cancers in which increasing the level of wild type p53proteins is not fruitful.

As used herein, the term p53 is directed to a p53 protein that can havea conformation of a WT p53, a mutated p53, or an intermediateconformation between WT and mutated p53.

As used herein, the terms “wild type p53”, “wt p53” and “WT p53” mayinterchangeably be used and are directed to a wild type p53 protein,having the conformation of a wild type p53 protein and hence, activityof a wild type p53 protein. In some embodiments, wild type p53 can beidentified by a specific monoclonal antibody.

As used herein, the terms “mutant p53”, “Mut-p53”, “mutated p53”, and“p53 mutant” may interchangeably be used and are directed to a mutatedp53 protein, incapable of efficiently functioning in a target cell. Insome embodiments, a Mut-p53 cannot bind its target site. In someembodiments, a Mut-p53 is mutated at the DNA binding domain (DBD)region. In some embodiments, a Mut-p53 is misfolded in an inactiveconformation. In some exemplary embodiments, the Mut-p53 is atemperature sensitive (ts) mut p53 R249S (R249S p53), a hot spot fulllength mutant p53 Mut-p53 R175H (R175H p53), or any other Mut-p53protein. In some embodiments, a Mut-p53 is identified by a specificmonoclonal antibody, capable of recognizing a misfolded conformation ofp53 (induced by the mutation of the p53). In some embodiments, a Mut-p53is identified by a specific monoclonal antibody.

The phrase “peptide reactivates a mutant p53 protein” as used hereinrefers to a peptide which upon its interaction with a mutant p53protein, the mutant p53 protein increases at least one of hisactivities, wherein the activities are the activities of a wild type p53protein. For example, upon its interaction with a peptide provided bythe present invention, a mutant p53 protein may increase, directly orindirectly, the expression of pro-apoptotic proteins such as caspases ina cancer cell, in a similar way to what would a wild type p53 protein doin a similar situation.

As referred to herein, the terms “reactivating peptide”, “Mut-p53reactivating peptide” may interchangeably be used and are directed to apeptidic agent capable of at least partially restoring activity toMut-p53. In some embodiments, the reactivating agent can reactivate aMut-p53 by affecting the conformation of the Mut-p53, to assume aconformation which is more similar to or identical to a native, WT p53.In some embodiments, the reactivating agent can reactivate a Mut-p53 torestore binding of the Mut-p53 to a WT p53 binding site in a target DNA.In some embodiments, the reactivating agent can restore biochemicalproperties of the Mut-p53. In some embodiments, the reactivating agentcan induce the Mut-p53 protein to exhibit p53-selective inhibition ofcancer cells. In some embodiments, the reactivating agent can reactivatea Mut-p53 to have structural properties, biochemical properties,physiological properties and/or functional properties similar to oridentical to a WT p53 protein. In some embodiments, the reactivatingagent is a peptide. In some embodiments, the reactivating agent is apeptide having 5-20 amino acids in length. In some embodiments, thereactivating agent is a peptide having 6-10 amino acids in length.

The term “conformation” with respect to a protein is directed to thestructural arrangement (folding) of a protein in space.

A “pharmaceutical composition” refers to a composition suitable forpharmaceutical use in an animal or human. A pharmaceutical compositioncomprises a pharmacologically and/or therapeutically effective amount ofan active agent and a pharmaceutically acceptable carrier.Pharmaceutical compositions of the present invention and methods fortheir preparation will be readily apparent to those skilled in the art.Such compositions and methods for their preparation may be found, forexample, in Remington's Pharmaceutical Sciences, 19th Edition (MackPublishing Company, 1995). The pharmaceutical compositions are generallyformulated as sterile, substantially isotonic and in full compliancewith all GMP regulations of the U.S. Food and Drug Administration. Theterm also encompasses any of the agents listed in the US Pharmacopeiafor use in animals, including humans. Suitable pharmaceutical carriersand formulations are described in Remington's Pharmaceutical Sciences,21st Ed. 2005, Mack Publishing Co, Easton.

“Pharmaceutically acceptable carrier” refers to compositions that do notproduce adverse, allergic, or other untoward reactions when administeredto an animal or a human. As used herein, “pharmaceutically acceptablecarrier” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents, and the like that are physiologically compatible. Some examplesof pharmaceutically acceptable carriers are water, saline, phosphatebuffered saline, dextrose, glycerol, ethanol and the like, as well ascombinations thereof. In many cases, the composition will includeisotonic agents, for example, sugars, polyalcohols such as mannitol,sorbitol, or sodium chloride in the composition. Additional examples ofpharmaceutically acceptable substances are wetting agents or minoramounts of auxiliary substances such as wetting or emulsifying agents,preservatives or buffers, which enhance the shelf life or effectivenessof the peptide of the invention.

As used herein the term “pharmaceutically acceptable salt” refers tosalts of peptides that retain the biological activity of the parentpeptide, and which are not biologically or otherwise undesirable. Manyof the compounds disclosed herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable base addition saltscan be prepared from inorganic and organic bases. Salts derived frominorganic bases, include by way of example only, sodium, potassium,lithium, ammonium, calcium and magnesium salts. Salts derived fromorganic bases include, but are not limited to, salts of primary,secondary and tertiary amines.

As used herein, a “therapeutically effective amount” of a peptide thatwhen provided to a subject in accordance with the disclosed and claimedmethods effects biological activities such as modulating cell signalingassociated with aberrant cellular proliferation and malignancy,impacting cell viability.

The terms “treat”, “treating” and “treatment” refer refers to anapproach for obtaining beneficial or desired clinical results. Further,references herein to “treatment” include references to curative,palliative and prophylactic treatment. The term “treating” refers toinhibiting, preventing or arresting the development of a pathology(disease, disorder or condition) and/or causing the reduction,remission, or regression of a pathology. Those of skill in the art willunderstand that various methodologies and assays can be used to assessthe development of a pathology, and similarly, various methodologies andassays may be used to assess the reduction, remission or regression of apathology.

For clarity, the term “instructing” is meant to include information on alabel approved by a regulatory agency, in addition to its commonlyunderstood definition.

As used herein and in the appended claims, the singular forms “a,” “or,”and “the” include plural referents unless the context clearly dictatesotherwise. It is understood that aspects and variations of thedisclosure described herein include “consisting” and/or “consistingessentially of” aspects and variation.

The term “about” as used herein means greater or lesser than the valueor range of values stated by 10 percent, but is not intended todesignate any value or range of values to only this broader definition.Each value or range of values preceded by the term “about” is alsointended to encompass the embodiment of the stated absolute value orrange of values.

As used herein, the term “preventing” refers to keeping a disease,disorder or condition from occurring in a subject who may be at risk forthe disease, but has not yet been diagnosed as having the disease.

As used herein, the term “subject” includes mammals, preferably humanbeings at any age which suffer from the pathology. Preferably, this termencompasses individuals who are at risk to develop the pathology.

The pharmaceutical compositions of the present invention are typicallysuitable for parenteral administration. As used herein, “parenteraladministration” of a pharmaceutical composition includes any route ofadministration characterized by physical breaching of a tissue of asubject and administration of the pharmaceutical composition through thebreach in the tissue, thus generally resulting in the directadministration into the blood stream, into muscle, or into an internalorgan. Parenteral administration thus includes, but is not limited to,administration of a pharmaceutical composition by injection of thecomposition, by application of the composition through a surgicalincision, by application of the composition through a tissue-penetratingnon-surgical wound, and the like. In particular, parenteraladministration is contemplated to include, but is not limited to,subcutaneous injection, intraperitoneal injection, intramuscularinjection, intrasternal injection, intravenous injection, intraarterialinjection, intrathecal injection, intraventricular injection,intraurethral injection, intracranial injection, intrasynovial injectionor infusions; or kidney dialytic infusion techniques.

In various embodiments, the peptide is admixed with a pharmaceuticallyacceptable carrier to form a pharmaceutical composition that can besystemically administered to the subject orally or via intravenousinjection, intramuscular injection, subcutaneous injection,intraperitoneal injection, transdermal injection, intra-arterialinjection, intrasternal injection, intrathecal injection,intraventricular injection, intraurethral injection, intracranialinjection, intrasynovial injection or via infusions. The pharmaceuticalcomposition preferably contains at least one component that is not foundin nature.

Formulations of a pharmaceutical composition suitable for parenteraladministration typically generally comprise the active ingredientcombined with a pharmaceutically acceptable carrier, such as sterilewater or sterile isotonic saline. Such formulations may be prepared,packaged, or sold in a form suitable for bolus administration or forcontinuous administration. Injectable formulations may be prepared,packaged, or sold in unit dosage form, such as in ampoules or inmulti-dose containers containing a preservative. Such unit dosage formsand multi-dose containers, optionally containing a preservative, areadditional aspects of the invention. Formulations for parenteraladministration include, but are not limited to, suspensions, solutions,emulsions in oily or aqueous vehicles, pastes, and the like. Suchformulations may further comprise one or more additional ingredientsincluding, but not limited to, suspending, stabilizing, or dispersingagents. In one embodiment of a formulation for parenteraladministration, the active ingredient is provided in dry (i.e. powder orgranular) form for reconstitution with a suitable vehicle (e.g. sterilepyrogen-free water) prior to parenteral administration of thereconstituted composition. Parenteral formulations also include aqueoussolutions which may contain carriers such as salts, carbohydrates andbuffering agents (preferably to a pH of from 3 to 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as a dried form to be used in conjunction with asuitable vehicle such as sterile, pyrogen-free water. Exemplaryparenteral administration forms include solutions or suspensions insterile aqueous solutions, for example, aqueous propylene glycol ordextrose solutions. Such dosage forms can be suitably buffered, ifdesired. Other parentally-administrable formulations which are usefulinclude those which comprise the active ingredient in microcrystallineform, or in a liposomal preparation. Formulations for parenteraladministration may be formulated to be immediate and/or modifiedrelease. Modified release formulations include delayed-, sustained-,pulsed-, controlled-, targeted and programmed release.

Transdermal administration is a still further option, e.g. byneedle-free injection, from a patch such as an iontophoretic patch, orvia a transmucosal route, e.g. buccally. The present invention includescompositions and methods for transdermal or topical delivery, to actlocally at the point of application, or to act systemically onceentering the body's blood circulation. In these systems, delivery may beachieved by techniques such as direct topical application of a substanceor drug in the form of an ointment or the like, or by adhesion of apatch with a reservoir or the like that holds the drug (or othersubstance) and releases it to the skin in a time-controlled fashion. Fortopical administration, the compositions of the present invention can bein the form of emulsions, lotions, gels, creams, jellies, solutions,suspensions, ointments, and transdermal patches. Some topical deliverycompositions may contain polyenylphosphatidylcholine (herein abbreviated“PPC”). In some cases, PPC can be used to enhance epidermal penetration.The term “polyenylphosphatidylcholine,” as used herein, means anyphosphatidylcholine bearing two fatty acid moieties, wherein at leastone of the two fatty acids is an unsaturated fatty acid with at leasttwo double bonds in its structure, such as linoleic acid. Such topicalformulations may comprise one or more emulsifiers, one or moresurfactants, one or more polyglycols, one or more lecithins, one or morefatty acid esters, or one or more transdermal penetration enhancers.Preparations can include sterile aqueous or nonaqueous solutions,suspensions and emulsions, which can be isotonic with the blood of thesubject in certain embodiments. Examples of nonaqueous solvents arepolypropylene glycol, polyethylene glycol, vegetable oil such as oliveoil, sesame oil, coconut oil, arachis oil, peanut oil, mineral oil,organic esters such as ethyl oleate, or fixed oils including syntheticmono or di-glycerides. Aqueous solvents include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution,1,3-butandiol, Ringer's dextrose, dextrose and sodium chloride, lactatedRinger's or fixed oils. Intravenous vehicles include fluid and nutrientreplenishers, electrolyte replenishers (such as those based on Ringer'sdextrose), and the like. Preservatives and other additives may also bepresent such as, for example, antimicrobials, antioxidants, chelatingagents and inert gases and the like.

For example, in one aspect, sterile injectable solutions can be preparedby incorporating a peptide in the required amount in an appropriatesolvent with one or a combination of ingredients enumerated above, asrequired, followed by filtered sterilization. Generally, dispersions areprepared by incorporating the active compound into a sterile vehiclethat contains a basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile powdersfor the preparation of sterile injectable solutions, methods ofpreparation such as vacuum drying and freeze-drying yield a powder ofthe active ingredient plus any additional desired ingredient from apreviously sterile-filtered solution thereof. The proper fluidity of asolution can be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersion and by the use of surfactants. Prolonged absorption ofinjectable compositions can be brought about by including in thecomposition an agent that delays absorption, for example, monostearatesalts and gelatin. In various embodiments, the injectable compositionswill be administered using commercially available disposable injectabledevices.

The parenteral formulations can be presented in unit-dose or multi-dosesealed containers, such as ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example, water, for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions can be prepared from sterile powders, granules, and tabletsof the kind known in the art. Injectable formulations are in accordancewith the invention. The requirements for effective pharmaceuticalcarriers for injectable compositions are well-known to those of ordinaryskill in the art (see, e.g., Pharmaceutics and Pharmacy Practice, J. B.Lippincott Company, Philadelphia, Pa., Banker and Chalmers, eds., pages238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed.,pages 622-630 (1986)).

Additionally, the peptides of the present disclosures can be made intosuppositories for rectal administration by mixing with a variety ofbases, such as emulsifying bases or water-soluble bases. Formulationssuitable for vaginal administration can be presented as pessaries,tampons, creams, gels, pastes, foams, or spray formulas containing, inaddition to the active ingredient, such carriers as are known in the artto be appropriate.

It will be appreciated by one of skill in the art that, in addition tothe above-described pharmaceutical compositions, the peptides of thedisclosure can be formulated as inclusion complexes, such ascyclodextrin inclusion complexes, or liposomes.

The peptide of the present invention can be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, or as a mixed component particle, for example, mixed with asuitable pharmaceutically acceptable carrier) from a dry powder inhaler,as an aerosol spray from a pressurized container, pump, spray, atomiser(preferably an atomiser using electrohydrodynamics to produce a finemist), or nebulizer, with or without the use of a suitable propellant,or as nasal drops. The pressurized container, pump, spray, atomizer, ornebulizer generally contains a solution or suspension of a peptide ofthe invention comprising, for example, a suitable agent for dispersing,solubilizing, or extending release of the active, a propellant(s) assolvent. Prior to use in a dry powder or suspension formulation, thedrug product is generally micronized to a size suitable for delivery byinhalation (typically less than 5 microns). This may be achieved by anyappropriate comminuting method, such as spiral jet milling, fluid bedjet milling, supercritical fluid processing to form nanoparticles, highpressure homogenization, or spray drying. Capsules, blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the peptide of the invention, a suitable powderbase and a performance modifier. Suitable flavors, such as menthol andlevomenthol, or sweeteners, such as saccharin or saccharin sodium, maybe added to those formulations of the invention intended forinhaled/intranasal administration. Formulations for inhaled/intranasaladministration may be formulated to be immediate and/or modifiedrelease. Modified release formulations include delayed-, sustained-,pulsed-, controlled-, targeted and programmed release. In the case ofdry powder inhalers and aerosols, the dosage unit is determined by meansof a valve which delivers a metered amount. Units in accordance with theinvention are typically arranged to administer a metered dose or “puff”of a peptide of the invention. The overall daily dose will typically beadministered in a single dose or, more usually, as divided dosesthroughout the day.

In some embodiments, the peptides (particularly peptide comprised whollyof naturally occurring acids for which codons exist) may be administeredas their nucleotide equivalents via gene therapy methods. Thepolynucleotides that encode the peptides, vectors, and recombinant hostcells also are embodiments of the invention.) In one embodiment, thepeptide-related polynucleotide is encoded or inserted in a plasmid orvector, which may be derived from an adeno-associated virus (AAV). TheAAV may be a recombinant AAV virus and may comprise a capsid serotypesuch as, but not limited to, of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6,AAV7, AAV8, AAV9, AAV9.47, AAV9(hu14), AAV10, AAV11, AAV12, AAVrh8,AAVrh10, AAV-DJ, and AAV-DJ8. As a non-limiting example, the capsid ofthe recombinant AAV virus is AAV2. As a non-limiting example, the capsidof the recombinant AAV virus is AAVrh10. As a non-limiting example, thecapsid of the recombinant AAV virus is AAV9(hu 14). As a non-limitingexample, the capsid of the recombinant AAV virus is AAV-DJ. As anon-limiting example, the capsid of the recombinant AAV virus isAAV9.47. As a non-limiting example, the capsid of the recombinant AAVvirus is AAV-DJ8. An embodiment comprises the nucleotide equivalents ofthe peptide sequences described herein whose complete sequence isencoded by codons of the genetic code.

A person skilled in the art may recognize that a target cell may requirea specific promoter including but not limited to a promoter that isspecies specific, inducible, tissue-specific, or cell cycle-specificParr et al, Nat. Med. 3:1145-9 (1997); the contents of which are hereinincorporated by reference in its entirety).

As used herein, a “vector” is any molecule or moiety which transports,transduces or otherwise acts as a carrier of a heterologous moleculesuch as the polynucleotides of the invention. A “viral vector” is avector which comprises one or more polynucleotide regions encoding orcomprising payload molecule of interest, e.g., a transgene, apolynucleotide encoding a polypeptide or multi-polypeptide. Viralvectors of the present invention may be produced recombinantly and maybe based on adeno-associated virus (AAV) parent or reference sequence.Serotypes which may be useful in the present invention include any ofthose arising from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9,AAV9.47, AAV9(hu14), AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAV-DJ, andAAV-DJ8.

In one embodiment, the serotype which may be useful in the presentinvention may be AAV-DJ8. The amino acid sequence of AAV-DJ8 maycomprise two or more mutations in order to remove the heparin bindingdomain (HBD). As a non-limiting example, the AAV-DJ sequence describedas SEQ ID NO: 1 in U.S. Pat. No. 7,588,772, the contents of which areherein incorporated by reference in its entirety, may comprise twomutations: (1) R587Q where arginine (R; arg) at amino acid 587 ischanged to glutamine (Q; gln) and (2) R590T where arginine (R; arg) atamino acid 590 is changed to threonine (T; thr). As another non-limitingexample, may comprise three mutations: (1) K406R where lysine (K; lys)at amino acid 406 is changed to arginine (R; arg), (2) R587Q wherearginine (R; arg) at amino acid 587 is changed to glutamine (Q; gln) and(3) R590T where arginine (R; arg) at amino acid 590 is changed tothreonine (T; thr).

AAV vectors may also comprise self-complementary AAV vectors (scAAVs).scAAV vectors contain both DNA strands which anneal together to formdouble stranded DNA. By skipping second strand synthesis, scAAVs allowfor rapid expression in the cell.

In one embodiment, the pharmaceutical composition comprises arecombinant adeno-associated virus (AAV) vector comprising an AAV capsidand an AAV vector genome. The AAV vector genome may comprise at leastone peptide-related polynucleotide described herein. The recombinant AAVvectors in the pharmaceutical composition may have at least 70% whichcontain an AAV vector genome.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods forthe delivery of AAV virions described in European Patent Application No.EP1857552, the contents of which are herein incorporated by reference inits entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering proteins using AAV vectors described in European PatentApplication No. EP2678433, the contents of which are herein incorporatedby reference in its entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering DNA molecules using AAV vectors described in U.S. Pat. No.5,858,351, the contents of which are herein incorporated by reference inits entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering DNA to the bloodstream described in U.S. Pat. No. 6,211,163,the contents of which are herein incorporated by reference in itsentirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering AAV virions described in U.S. Pat. No. 6,325,998, thecontents of which are herein incorporated by reference in its entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering a payload to the central nervous system described in U.S.Pat. No. 7,588,757, the contents of which are herein incorporated byreference in its entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering a payload described in U.S. Pat. No. 8,283,151, the contentsof which are herein incorporated by reference in its entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering a payload using a glutamic acid decarboxylase (GAD) deliveryvector described in International Patent Publication No. WO 2001/089583,the contents of which are herein incorporated by reference in itsentirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering a payload to neural cells described in International PatentPublication No. WO 2012/057363, the contents of which are hereinincorporated by reference in its entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering a payload to cells described in U.S. Pat. No. 9,585,971, thecontents of which are herein incorporated by reference in its entirety.

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods fordelivering a payload to cells described in Deverman et al. NatureBiotechnology, 34, 204-09 (2016).

In one embodiment, the viral vector comprising a peptide-relatedpolynucleotide may be administered or delivered using the methods forthe delivery of AAV virions described in U.S. Pat. No. 7,198,951[adeno-associated virus (AAV) serotype 9 sequences, vectors containingsame, and uses therefor], U.S. Pat. No. 9,217,155 [isolation of novelAAV's and uses thereof], WO 2011/126808 [pharmacologically inducedtransgene ablation system], U.S. Pat. No. 6,015,709 [transcriptionalactivators, and compositions and uses related thereto], U.S. Pat. No.7,094,604 [Production of pseudotyped recombinant AAV virions], WO2016/126993 [anti-tau constructs], U.S. Pat. No. 7,094,604 [recombinantAAV capsid protein], U.S. Pat. No. 8,292,769 [Avian adeno associatedviru (aaav) and uses thereof], U.S. Pat. No. 9,102,949 [CNS targetingAAV vectors and methods of use thereof], US 2016-0120960[adeno-associated virus mediated gene transfer to the central nervoussystem], WO 2016/073693 [AADC polynucleotides for the treatment ofparkinson's disease], WO 2015/168666 [AAV VECTORS FOR RETINAL AND CNSGENE Therapy], US 2009-0117156 [Gene Therapy for Niemann-Pick Diseasetype A] or WO 2005/120581 [gene therapy for neurometabolic disorders].

Pharmaceutical compositions intended for transderman use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions.

According to one aspect, the compounds of the invention are for use inmedicine, particularly human medicine. The peptides are effective totreat p53 related diseases. In addition to p53, the peptides bind to p63and p73. Therefore, these peptides have utility in treating diseasesimpacted by those two proteins.

The present invention also includes methods of treating cancercomprising administering an effective amount of a peptide or a variantthereof to a subject in need of treatment. The peptides provided hereinexert a variety of anticancer effects and can be used to treat a widerange of cancers and other proliferative disorders. Peptides providedherein can have a variety of anticancer activities, such as but notlimited to, inducing apoptosis in cancerous cells, inhibiting tumorangiogenesis, inhibiting tumor metastasis, modulating the cell cycle,inhibiting cancer cell proliferation, promoting cancer celldifferentiation, inhibiting production of and/or protecting againstreactive oxygen species, and enhancing stress resistance. The term“cancer” means a disease in mammals that is characterized byuncontrolled, abnormal cell growth and proliferation. General classes ofcancers include carcinomas, lymphomas, sarcomas, and blastemas. A“tumor” or “neoplasm” is an abnormal mass of tissue that results fromexcessive, un controlled, and progressive cell division. Methodsdescribed herein are useful for treating cancers and proliferativedisorders of any type, including but not limited to, carcinomas,sarcomas, soft tissue sarcomas, lymphomas, hematological cancers,leukemias, germ cell tumors, and cancers without solid tumors (e.g.,hematopoietic cancers). In various aspects, the peptides can be used totreat cancers and/or tumors originating from and/or effecting anytissue, including but not limited to, lung, breast, epithelium, largebowel, rectum, testicle, bladder, thyroid, gallbladder, bile duct,biliary tract, prostate, colon, stomach, esophagus, pancreas, liver,kidney, uterus, cervix, ovary, and brain tissues. Non-limiting examplesof specific cancers treatable with the peptides include, but are notlimited to, acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia,adrenocortical carcinoma, AIDS-related lymphoma, anal cancer,astrocytoma, cerebral basal cell carcinoma, bile duct cancer,extrahepatic bladder cancer, bladder cancer, bone cancer,osteosarcoma/malignant fibrous histiocytoma, brain stem glioma, braintumor, brain stem glioma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodermaltumor, visual pathway and hypothalamic glioma, breast cancer, malebronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor,gastrointestinal carcinoma of unknown primary central nervous systemlymphoma, cervical cancer, chronic lymphocytic leukemia, chronicmyelogenous leukemia, chronic myeloproliferative disorders, coloncancer, colorectal cancer, cutaneous t-cell lymphoma, mycosis fungoidesand sezary syndrome, endometrial cancer, ependymoma, esophageal cancer,Ewing's family tumors, germ cell tumors, extrahepatic bile duct cancer,eye cancer, intraocular melanoma, retinoblastoma, gallbladder cancer,gastric (stomach) cancer, gastrointestinal carcinoid tumors, ovariangestational, trophoblastic tumors, glioma, hypothalamic skin cancer(melanoma), skin cancer (non-melanoma), skin carcinoma, small cell lungcancer, small intestine cancer, soft tissue sarcoma, squamous cellcarcinoma, squamous neck cancer with occult primary, metastatic stomach(gastric) cancer, stomach (gastric) cancer, t-cell lymphoma, testicularcancer, thymoma, thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis, ureter trophoblastic tumors, transitionalcell cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, hypothalamic glioma, vulvar cancer, Waldenstrom'smacroglobulinemia, Wilms' tumor, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer. Hodgkin's lymphoma,hypopharyngeal cancer, islet cell carcinoma (endocrine pancreas),Kaposi's sarcoma, kidney (renal cell) cancer, kidney cancer, laryngealcancer, hairy cell lip and oral cavity cancer, liver cancer, lungcancer, non-small cell lung cancer, small cell lymphoma, Burkitt'slymphoma, cutaneous t-cell, Hodgkin's lymphoma, non-Hodgkin's lymphoma,Waldenstrom's malignant fibrous histiocytoma of bone/osteosarcomamedulloblastoma, intraocular (eye) merkel cell carcinoma, mesothelioma,malignant mesothelioma, metastatic squamous neck cancer with occultprimary multiple endocrine neoplasia syndrome, multiple myeloma/plasmacell neoplasm, mycosis fungoides myelodysplastic syndromes,myelodysplastic/myeloproliferative diseases, myelogenous leukemia,multiple myeloproliferative disorders, chronic nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, pleoropulmonary blastoma,osteosarcoma/malignant fibrous histiocytoma of bone, phceochromocytoma,pineoblastoma, and supratentorial primitive neuroectodermal tumors. Insome preferred aspects, the cancer is breast cancer. In some preferredaspects, the cancer is prostate cancer.

In some embodiments of the invention, the peptides have anticanceractivity. For example, in some aspects, the peptides have activityagainst cancer cells, such as but not limited to, ovarian cancer cells.In further aspects, the peptides have anti-proliferative activityagainst cancer cells, such as but not limited to, ovarian cancer cells.

In some embodiments of the invention, the peptides provided herein haveanticancer activity in vivo. For example, in some aspects, the peptideshave growth inhibitory activity against tumors in vivo. In furtheraspects, the peptides increase apoptosis, decreased angiogenesis, and/orreduce proliferation of tumors and/or tumor cells and growth of tumors.

According to another embodiment, the agents of the present invention arecoadministered or co-formulated with other known chemotherapeutic agentsand/or antiinflammatory agents. The invention also concerns the use ofthe compound of the present invention in the manufacture of a medicamentfor the treatment of a condition such as a cancer.

The compound of the present invention, or the pharmaceuticallyacceptable salts thereof, may also be administered in combination withone or more additional pharmaceutically active compounds/agents, in aparticular embodiment, the additional pharmaceutically active agent isan agent that can be used to treat a cancer. For example, an additionalpharmaceutically active agent can be selected from antineoplasticagents, anti-angiogenic agents, chemotherapeutic agents and peptidalcancer therapy agents, in yet another embodiment, the antineoplasticagents are selected from antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents, kinase inhibitors, miscellaneous agents andcombinations thereof. It is noted that the additional pharmaceuticallyactive compounds/agents may be a traditional small organic chemicalmolecules or can he macromolecules such as a proteins, antibodies,peptibodies, DNA, RNA or fragments of such macromolecules.

Examples of specific pharmaceutically active agents that can be used incombination with one or more peptides of the present invention include:atezolizumab, pembrolizumab, ipilimumab, methotrexate; tamoxifen;fluorouracil; 5-fluorouracil; hydroxyurea; mercaptopurine: cispiatin;carboplatin; daunorubicin; doxorubicin; etoposide; vinblastine;vincristine; pacitaxei; thioguanine; idarubicin; dactinomycin; imatinib;gemcitabine; altretamine; asparaginase; bleomycin; capecitabine;carmustine; cladisat, aq. NaCl solution; cyclophosphamine; cytarabine;decarazine; docetaxel; idarubicin; ifosfamide; irinotecan; fludarabine;mitosmycin; mitoxane; mitoxantrone; topotecan; vinoreibine; adriamycin;mithram; imiquimod; alemtuzmab; exemestane; bevacizumab; cetuximab;azacitidine; clofarabine; decitabine; desatinib; dexrazoxane; docetaxel;epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole;gefitinib; gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib;lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib;nilotinib; pegaspargase; pemetrexed; rituximab; dasati ib; thalidomide;bexarotene; temsirolimus; bortezomib; vorinostat; capecitabine;zoledronic acid; anastrozole; sunitinib; aprepitant and nelarabine, or apharmaceutically acceptable salt thereof.

The compound of the present invention may also be used in combinationwith radiation therapy, hormone therapy, surgery and immunotherapy,which therapies are well known to those skilled in the art.

Since one aspect of the present invention contemplates the treatment ofthe disease/conditions with a combination of pharmaceutically activecompounds that may be administered separately, the invention furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: the compoundof the present invention, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes and bags. Typically, the kitcomprises directions for the use of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician or veterinarian.

Thus, the skilled artisan would appreciate, based upon the disclosureprovided herein, that the dose and dosing regimen is adjusted inaccordance with methods well-known in the therapeutic arts. That is, themaximum tolerable dose can be readily established, and the effectiveamount providing a detectable therapeutic benefit to a subject may alsobe determined, as can the temporal requirements for administering eachagent to provide a detectable therapeutic benefit to the subject.Accordingly, while certain dose and administration regimens areexemplified herein, these examples in no way limit the dose andadministration regimen that may be provided to a subject in practicingthe present disclosure. Treatment of a subject with a therapeuticallyeffective amount of a peptide, of the invention can include a singletreatment or, preferably, can include a series of treatments. In apreferred example, a subject is treated with peptide daily, one time perweek or biweekly.

It is to be noted that dosage values may vary with the type and severityof the condition to be ameliorated, and may include single or multipledoses. It is to be further understood that for any particular subject,specific dosage regimens should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition.Further, the dosage regimen with the compositions of this disclosure maybe based on a variety of factors, including the type of disease, theage, weight, sex, medical condition of the subject, the severity of thecondition, the route of administration, and the particular antibodyemployed. Thus, the dosage regimen can vary widely, but can bedetermined routinely using standard methods. For example, doses may beadjusted based on pharmacokinetic or pharmacodynamic parameters, whichmay include clinical effects such as toxic effects and/or laboratoryvalues. Thus, the present disclosure encompasses intra-subjectdose-escalation as determined by the skilled artisan. Determiningappropriate dosages and regimens are well-known in the relevant art andwould be understood to be encompassed by the skilled artisan onceprovided the teachings disclosed herein.

The dose of the peptide of the present disclosure also will bedetermined by the existence, nature and extent of any adverse sideeffects that might accompany the administration of a particular peptideof the present disclosure. Typically, the attending physician willdecide the dosage of the peptide of the present disclosure with which totreat each individual patient, taking into consideration a variety offactors, such as age, body weight, general health, diet, sex, peptide ofthe present disclosure to be administered, route of administration, andthe severity of the condition being treated. By way of example and notintending to limit the invention, the dose of the peptide of the presentdisclosure can be about 0.0001 to about 100 mg/kg body weight of thesubject being treated/day. The peptide can be administered in one ormore doses, such as from 1 to 3 doses.

In some embodiments, the pharmaceutical composition comprises any of theanalogs disclosed herein at a purity level suitable for administrationto a patient. In some embodiments, the analog has a purity level of atleast about 90%, preferably above about 95%, more preferably above about99%, and a pharmaceutically acceptable diluent, carrier or excipient.

The pharmaceutical compositions may be formulated to achieve aphysiologically compatible pH. In some embodiments, the pH of thepharmaceutical composition may be at least 5, or at least 6, or at least7, depending on the formulation and route of administration.

In various embodiments, single or multiple administrations of thepharmaceutical compositions are administered depending on the dosage andfrequency as required and tolerated by the subject. In any event, thecomposition should provide a sufficient quantity of at least one of thepeptide disclosed herein to effectively treat the subject. The dosagecan be administered once but may be applied periodically until either atherapeutic result is achieved or until side effects warrantdiscontinuation of therapy.

The dosing frequency of the administration of the peptide pharmaceuticalcomposition depends on the nature of the therapy and the particulardisease being treated. Treatment of a subject with a therapeuticallyeffective amount of a peptide, of the invention can include a singletreatment or, preferably, can include a series of treatments. In apreferred example, a subject is treated with peptide daily, one time perweek or biweekly.

The invention having been described, the following examples are offeredby way of illustration, and not limitation.

EXAMPLES

The present disclosures provide peptides comprising a variety ofsequences.

Example 1

The peptides of the invention are prepared via solid phase synthesis ona suitable resin using t-Boc or Fmoc chemistry or other well establishedtechniques, (see for example: Stewart and Young, Solid Phase PeptideSynthesis, Pierce Chemical Co., Rockford, III., 1984; E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis. A Practical Approach,Oxford-IRL Press, New York, 1989; Greene and Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons, 1999, Florencio Zaragoza Dorwald,“Organic Synthesis on solid Phase”, Wiley-VCH Verlag GmbH, 2000, and“Fmoc Solid Phase Peptide Synthesis”, Edited by W. C. Chan and P. D.White, Oxford University Press, 2000) by a method similar to thatdescribed below, unless specified otherwise.

Solid phase synthesis is initiated by attaching an N-terminallyprotected amino acid with its carboxy terminus to an inert solid supportcarrying a cleavable linker. This solid support can be any polymer thatallows coupling of the initial amino acid, e.g. a Pam resin, tritylresin, a chlorotrityl resin, a Wang resin or a Rink resin in which thelinkage of the carboxy group (or carboxamide for Rink resin) to theresin is sensitive to acid (when Fmoc strategy is used). The polymersupport is stable under the conditions used to deprotect the α-aminogroup during the peptide synthesis. After the first amino acid has beencoupled to the solid support, the α-amino protecting group of this aminoacid is removed. The remaining protected amino acids are then coupledone after the other in the order represented by the peptide sequenceusing appropriate amide coupling reagents, for example BOP(benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium), HBTU(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium), HATU(O-(7-azabenztriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium) or DIC(N,N′-diisopropylcarbodiimide)/HOBt (1-hydroxybenzotriazol), whereinBOP, HBTU and HATU are used with tertiary amine bases. Alternatively,the liberated N-terminus can be functionalized with groups other thanamino acids, for example carboxylic acids, etc. Usually, reactiveside-chain groups of the amino acids are protected with suitableblocking groups. These protecting groups are removed after the desiredpeptides have been assembled. They are removed concomitantly with thecleavage of the desired product from the resin under the sameconditions. Protecting groups and the procedures to introduce protectinggroups can be found in Protective Groups in Organic Synthesis, 3d ed.,Greene, T. W. and Wuts, P. G. M., Wiley & Sons (New York: 1999). In somecases it might be desirable to have side-chain protecting groups thatcan selectively be removed while other side-chain protecting groupsremain intact. In this case the liberated functionality can beselectively functionalized. For example, a lysine may be protected withan ivDde protecting group (S. R. Chhabra et al., Tetrahedron Lett. 39,(1998), 1603) which is labile to a very nucleophilic base, for example4% hydrazine in DMF (dimethyl formamide). Thus, if the N-terminal aminogroup and all side-chain functionalities are protected with acid labileprotecting groups, the ivDde([1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl) group canbe selectively removed using 4% hydrazine in DMF and the correspondingfree amino group can then be further modified, e.g. by acylation. Thelysine can alternatively be coupled to a protected amino acid and theamino group of this amino acid can then be deprotected resulting inanother free amino group which can be acylated or attached to furtheramino acids. Finally the peptide is cleaved from the resin. This can beachieved by using HF or King's cocktail (D. S. King, C. G. Fields, G. B.Fields, Int. J. Peptide Protein Res. 36, 1990, 255-266). The rawmaterial can then be purified by chromatography, e.g. preparativeRP-HPLC, if necessary.

Those peptides, analogs or derivatives of the invention which includenon-natural amino acids and/or a covalently attached N-terminal mono- ordipeptide mimetic may be produced as described in the experimental part.Or see e.g., Hodgson et al: “The synthesis of peptides and proteinscontaining non-natural amino acids”, and Chemical Society Reviews, vol.33, no. 7 (2004), p. 422-430.

The peptides are prepared according to the below-mentioned peptidesynthesis and the peptides presented in the Table 1 can be preparedsimilar to the below-mentioned synthesis, unless specified otherwise.

One method of peptide synthesis is by Fmoc chemistry on amicrowave-based Liberty peptide synthesizer (CEM Corp., North Carolina).The resin is Tentagel S RAM with a loading of about 0.25 mmol/g orPAL-ChemMatrix with a loading of about 0.43 mmol/g or PAL AM matrix witha loading of 0.5-0.75 mmol/g. The coupling chemistry is DIC/HOAt orDIC/Oxyma in NMP or DMF using amino acid solutions of 0.3 M and a molarexcess of 6-8 fold. Coupling conditions are 5 minutes at up to 70° C.Deprotection is with 10% piperidine in NMP at up to 70° C. The protectedamino acids used are standard Fmoc-amino acids (supplied from e.g.Anaspec or Novabiochem or Protein Technologies).

Another method of peptide synthesis is by Fmoc chemistry on a Preludepeptide synthesizer (Protein Technologies, Arizona). The resin isTentagel S RAM with a loading of about 0.25 mmol/g or PAL-ChemMatrixwith a loading of about 0.43 mmol/g or PAL AM with a loading of 0.5-0.75mmol/g. The coupling chemistry is DIC/HOAt or DIC/Oxyma in NMP or DMFusing amino acid solutions of 0.3 M and a molar excess of 6-8 fold.Coupling conditions are single or double couplings for 1 or 2 hours atroom temperature. Deprotection is with 20% piperidine in NMP. Theprotected amino acids used are standard Fmoc-amino acids (supplied frome.g. Anaspec or Novabiochem or Protein Technologies). The crude peptidesare purified such as by semipreparative HPLC on a 20 mm×250 mm columnpacked with either 5 um or 7 um C-18 silica. Peptide solutions arepumped onto the HPLC column and precipitated peptides are dissolved in 5ml 50% acetic acid H₂O and diluted to 20 ml with H₂O and injected on thecolumn which then is eluted with a gradient of 40-60% CH₃CN in 0.1% TFA10 ml/min during 50 min at 40° C. The peptide containing fractions arecollected. The purified peptide is lyophilized after dilution of theeluate with water.

All peptides with C terminal amides described herein are prepared by amethod similar to described below unless specified otherwise. MBHA resin(4-methylbenzhydrylamine polystyrene resin is used during peptidesynthesis. MBHA resin, 100-180 mesh, 1% DVB cross-linked polystyrene;loading of 0.7-1.0 mmol/g), Boc-protected and Fmoc protected amino acidscan be purchased from Midwest Biotech. The solid phase peptide synthesesusing Boc-protected amino acids are performed on an Applied Biosystem430A Peptide Synthesizer. Fmoc protected amino acid synthesis isperformed using the Applied Biosystems Model 433 Peptide Synthesizer.

Synthesis of the peptides is performed on the Applied Biosystem Model430A Peptide Synthesizer. Synthetic peptides are constructed bysequential addition of amino acids to a cartridge containing 2 mmol ofBoc protected amino acid. Specifically, the synthesis is carried outusing Boc DEPBT-activated single couplings. At the end of the couplingstep, the peptidyl-resin is treated with TFA to remove the N-terminalBoc protecting group. It is washed repeatedly with DMF and thisrepetitive cycle is repeated for the desired number of coupling steps.After the assembly, the sidechain protection, Fmoc, is removed by 20%piperidine treatment and acylation was conducted using DIC. Thepeptidyl-resin at the end of the entire synthesis is dried by using DCM,and the peptide is cleaved from the resin with anhydrous HF. Thepeptidyl-resin is treated with anhydrous HF, and this typically yieldedapproximately 350 mg (˜50% yield) of a crude deprotected-peptide.Specifically, the peptidyl-resin (30 mg to 200 mg) is placed in thehydrogen fluoride (HF) reaction vessel for cleavage. 500 μL of p-cresolwas added to the vessel as a carbonium ion scavenger. The vessel isattached to the HF system and submerged in the methanol/dry ice mixture.The vessel is evacuated with a vacuum pump and 10 ml of HF is distilledto the reaction vessel. This reaction mixture of the peptidyl-resin andthe HF is stirred for one hour at 0° C., after which a vacuum isestablished and the HF is quickly evacuated (10-15 min). The vessel isremoved carefully and filled with approximately 35 ml of ether toprecipitate the peptide and to extract the p-cresol and small moleculeorganic protecting groups resulting from HF treatment. This mixture isfiltered utilizing a teflon filter and repeated twice to remove allexcess cresol. This filtrate is discarded. The precipitated peptidedissolves in approximately 20 ml of 10% acetic acid (aq). This filtrate,which contained the desired peptide, is collected and lyophilized.

Example 2

Nat forms aggregation related fibrils. Electronic miscroscopy images ofthe formation of fibrils from the aggregation of Nat1 is shown in FIG.3. Nat1 is dissolved in DMSO, then diluted and to a final concentrationof 200 μM in 150 mM NaCl. 50 mM Hepes pH7.3. The solution is incubatedat room temperature. Images are made on a FEI TF20 TEM.

Example 3

The peptides of the invention were tested in an in vitro Thiofiavin Taggregation assay [see WO2014/182961]. An increase in Thioflavin Tfluorescence is detected over time due to the formation of increasingamounts of amyloid to which the dye can specifically bind. The peptideis added in solution at different concentrations and is able to delaythe aggregation onset and lower the total amount of aggregates present,in a concentration dependent fashion. For the Nat1 Stock Solution, Nat(LTIITLE (SEQ ID NO: 225), >95% Pure, TFA salt) is dissolved at 8 mM in25 mM NaOH solution and kept at −80° C. Prior to the assay, it isdiluted to 1 mM in H₂O. The 2× Reaction Buffer is prepared with 200 mMSodium Phosphate, pH6.0, 500 mM Sodium Chloride and 200 μM Thioflavin T(ThT). 100 μL of 2× reaction buffer and 80 μL of H₂O are added to eachwell in black, clear-bottomed 96-well plate. Inhibitor peptides aredissolved in H₂O to appropriate concentrations to produce 6-points doseresponse curves. 10 μL of dissolved peptide or H₂O (control) is added toeach reaction well. 10 μL of 1 mM Nat1 peptide is added to each reactionwell (a final concentration of 50 μM). ThT fluorescence is monitored atroom temperature every minute for 2 hours with excitation and emissionwavelengths of 440 and 485 nm, respectively. IC₅₀ values are calculatedusing Graphpad Prism. The results are reported in Table 4.

TABLE 4 Thiofiavin T aggregation assay SEQ ID IC50 Peptide NO: (nM)IRIRHYR 11 14 IRIRAYR 13 23 IRIRRYR 12 27 Ile-homoArg-Ile-homoArg-Arg- 330 Tyr-Arg kfrfyhr 123 32 LRIRYWK 14 36 IRIRRAR 15 37Ile-Arg-Ile-homoArg-Arg-Tyr- 5 40 Arg rihyfrr 124 43 hwrwlrr 125 43IRIARYR 16 44 IRIRRYA 17 44 Ile-homoArg-Ile-homoArg-Arg- 6 49 Trp-Argrwrylrr 126 49 rfhyfrk 127 51 IRIYRYK 18 60 TRIRFYR 19 64Chg-Arg-Chg-Arg-Arg-Tyr-Arg 7 67 Ac-IRIRRYR-NH2 20 69 LYIRYLR 21 70LRIKYHR 22 71 klkklh 128 71 IAIRRYR 23 74 kwrwyrr 129 75 LRIRRYR 24 76LWIKYHR 25 76 IRIRRWR 26 76 rfyyhrr 130 76 wwrwyrr 131 78 LRIYRVR 27 81Ile-Arg-Chg-Arg-Arg-Tyr-Arg 8 81 rfyrrhr 132 81 WTIKLWH 28 84 kyrwyrh133 87 fwrwhr 134 88 LRIRFFR 29 90 LTIRYYK 30 93 qqryywr 135 95 hlriwrn136 97 YRLRYLR 31 99 LFRYYQK 32 100 LVIRYHR 33 101 ffrfhrr 137 104RFYRYLR 34 107 lwrryhr 138 108 rirwywk 139 110 yqwrhwr 140 112 rwywhhr141 115 sfwykrr 142 116 rfefrhr 143 117 yqyyyqr 144 118Ile-Arg-Phg-Arg-Arg-Tyr-Arg 2 124 LRI(N-Me)KYHR 35 125 rqwyhwr 145 132hqryywr 146 138 hwryhrr 147 139 IRIRHYRP 36 142 ARIRRYR 37 144 rwhwhwr148 145 LRLRHYR 38 146 fwrwhrr 149 147 LYIKYHR 39 148 YTRITYH 40 150ffrfhhr 150 151 LRIYHHK 41 152 IRLRRYR 42 153 rwrwhhr 151 156 hwrwywk152 159 fwrhkhr 153 161 fwrwhrr 149 164 qiryfrr 154 167 YRLRYVR 43 175fwrwarr 155 176 LYIRYTH 44 180 qfrmhhr 156 181 yqyyfwr 157 181 LRIRHYT45 182 FRIRRYR 46 185 swwfrhr 158 187 yqwryrr 159 191 hlryhrk 160 192LYIRLTH 47 192 yqwyrwq 161 194 lwrwyrr 162 194 LTIRLWH 48 198 rwrilqk163 199 LYIRTLH 49 203 WTIRYYK 50 203 IRIRRY 51 205 LFIKYHR 52 210rqhyrwr 164 210 TRIYRYK 53 213 WTIRYYH 54 214 rlhwkhh 165 215 rwmywqr166 216 LAIKYHR 55 220 WTRITLK 56 222 fwrwhra 167 228 LTIKLWH 57 232LLIKYHA 58 234 rqmqyrr 168 236 fwawhrr 169 239 WTRIYLH 59 240 rfyrhhr170 244 fwrwhar 171 245 hwrwrwr 172 245 krwrhqr 173 245 LRIRHVK 60 246wwrrhhr 174 247 LLIKYHR 61 248 IRIRRAA 62 248 kqwyhwr 175 252 LYIRTYH 63257 LLIKAHR 64 258 LTIKLWH 57 260 WYIRLWK 65 262 fwrhkhr 153 264 awrwhrr176 267 IYIYHQR 66 269 RLYIRLS 67 284 WYIRTYH 68 287 farwhrr 177 287WYIRLWH 69 288 fwrahrr 178 293 LTIRTWH 70 295 rqhyhwr 179 296 LLIKYAR 71301 swrwhhr 180 301 LYIRTWH 72 302 LYIRHK 73 316 LTIRLTH 74 329LR(N-Me)IKYHR 75 334 shwrrhr 181 338 ywqwrqs 182 338 yqwqyqr 183 354TLIIYHR 76 357 LYIFRHT 77 363 WYIRLTH 78 369 WTRILWH 79 398 TYIRYLR 80412 WTRIYYH 81 420 LTIMLWH 82 425 WTKITLH 83 427 LFIYYQR 84 440 IQIYRYK85 444 IRIRAAR 86 451 fwrwhaa 184 458 LYIRTYH 63 463 LLIAYHR 87 466wwrfhwr 185 472 WTIRYYH 54 473 LFIFYHR 88 476 IRVYKYS 89 480 LTIQLWH 90481 LLIKYHR 61 489 YYIRYYK 91 494 IRFRRYR 92 496 WRIRRYR 93 514 WTIMLWH94 525 LTIRTLH 95 537 ALIKYHR 96 629 LHIEHR 97 657 rlkwrw 186 702 IFVYHH98 703 qlkwlh 187 716 WTIKLTH 99 720 IHIEIK 100 723 WTIRTWH 101 784YTYMLWK 102 824 farahrr 188 906 LSIRQH 103 945 klkwlw 189 1063 IRARRYR104 1253 WTRITLE [Comparator] 237 1337 ilkwlw 190 1340 YYIRTYH 105 1598LTRITLE [Comparator] 238 1680 LLAKYHR 106 1726 IWIRRWR 107 1902 AYYYRHR108 2125 shwrhhr 191 2267 rqwyrwq 192 2720 qwrwrhr 193 3136 TYVYRRR 1093660 TRIYRVK 110 3742 TYIYRQR 111 5166 qvryhkn 194 5695Phg-Arg-Phg-Arg-Arg-Tyr-Arg 4 5951 klkwqw 195 7307 LTRILTH 112 7374ILRLYFR 113 8968 klkway 196 12555 rmwrhhr 197 13209 FFRLYLR 114 13418LTRILWH 115 16219 FRLYIH 116 16351 TFVFRHR 117 20308 qfhylcrr 198 23903rfhrhhr 199 30923 IRIRRYE 118 32799 hqrryqr 122 39070 YTIQLWH 119 45982

Example 4

The peptides are tested for p63 binding and p73 binding in an in vitroThiofiavin T aggregation assay. There are sequences in p63[RPILIIVTLE—SEQ ID NO: 226] and p73 [RPILIIITLE—SEQ ID NO: 227] thatexhibit high homology with the amyloid sequence found in p53[RPILTIITLE—SEQ ID NO: 228]. The addition of the 50 μM solutions of p63and p73 peptides to the reaction Buffer described in Example 3, formsamyloid (FIG. 1(a) and FIG. 1(b)). An increase in Thioflavin Tfluorescence is detected over time due to the formation of increasingamounts of amyloid to which the dye can specifically bind. The inhibitorpeptides of the current invention are added in solution at differentconcentrations and is able to delay the aggregation onset and lower thetotal amount of aggregates present, in a concentration dependentfashion. For the Nat1 Stock Solution, Nat1 (LTIITLE (SEQ ID NO:225), >95% Pure, TFA salt) is dissolved at 8 mM in 25 mM NaOH solutionand kept at −80° C. Prior to the assay, it is diluted to 1 mM in H₂O.The 2× Reaction Buffer is prepared with 200 mM Sodium Phosphate, pH6.0,500 mM Sodium Chloride and 200 μM Thioflavin T (ThT). 100 μL of 2×reaction buffer and 80 μL of H₂O are added to each well in black,clear-bottomed 96-well plate. Inhibitor peptides are dissolved in H₂O toappropriate concentrations to produce 6-points dose response curves. 10μL of dissolved peptide or H₂O (control) is added to each reaction well.10 μL of 1 mM Nat1 peptide is added to each reaction well (a finalconcentration of 50 μM). ThT fluorescence is monitored at roomtemperature every minute for 2 hours with excitation and emissionwavelengths of 440 and 485 nm, respectively. The results are found inFIG. 2(a) and FIG. 2(b).

Example 5

To render the inhibitors cell permeable, the peptides are fused toeither a nine-residue poly L-Arg tag or a nine-residue poly D-Arg tag,through one of several three-residue linkers, either L-RPI, D-RPI, orD-GGG. Cancer cell lines, e.g. OVCAR-3, and Detroit 562 are treated withthe peptide conjugates for 24 hours by the following method. OVCAR3 andDetroit-562 cells are grown in ATCC recommended growth media. Thepeptides were made in a 4 mM stock. Cells are plated in 96-well flatbottom clear plates at 7000 cells/well. After 24 hours, compounds areserially diluted in one-third [starting at 33 μM] or one-half [startingat 30 μM] dilutions in PrEGM media (Lonza). Growth media was removedfrom the wells and compound in PrEGM was added to 100 ul final volume.24 hours post-compound addition cell metabolism was measured by additionof 20 μl MTS solution (Promega, cell-titer 96 aqueous). Absorbance wasread at 490 nm following a 2 hour incubation and data was processed inPrism Graphpad to generate EC₅₀ values. The results are reported inTable 5.

TABLE 5 Cell Assay with CPP Linked peptides Stability % Protein in HumanEC₅₀ (μM) Binding Serum EC₅₀ (μM) Detroit- in Human (t1/2)  OVCAR3562 in SEQ Sequence Serum (min) in PrEGM PrEGM ID NO RRRRRRRRRRPILTRITLE 66 339  8  9 229 RRRRRRRRRRPIIRIRHYR  84  30  6  6 203RRRRRRRRRRPIIRIRHYP  83 295  6  7 204 PRRRRRRRRRRPIIRIRHYRP  89 116 1012 205 RRRRRRRRRRPIIRIRHYRP  81 124  7  7 206 PRRRRRRRRRRPILRIRYWKP  98200  5  5 207 PRRRRRRRRRRPITRIRFYRP  89 103  8  9 208PRRRRRRRRRRPIWTIKLWHP 100 ND  4  6 209 RRRRRRRRRRPIqqryywr  82 600 22 12210 RRRRRRRRRRPIyqwyrwq  98  50 10 13 211 RRRRRRRRRRPIkfrfyhr  81 265 1115 212 RRRRRRRRRRPIrfyyhrr  91  57 16  9 213 rrrrrrrrrrpiyqwyrwq 99 >24 hr  6  5 230 rrrrrrrrrgggyqwyrwq  89 >24 hr  6  8 231rrrrrrrrrrpikfrfyhr  86 >24 hr  4  5 232 rrrrrrrrrrpirihyfrr  93 >24 hr 4  5 233 rrrrrrrrrrpikwrwyrr  94 >24 hr  4  5 234 rrrrrrrrrrpihlriwrn 95 >24 hr  4  4 235 rrrrrrrrrrpihqrqyqr  12 >24 hr 27 35 236

All of the articles and methods disclosed and claimed herein can be madeand executed without undue experimentation in light of the presentdisclosure. While the articles and methods of this disclosure have beendescribed in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to the articlesand methods without departing from the spirit and scope of thedisclosure. All such variations and equivalents apparent to thoseskilled in the art, whether now existing or later developed, are deemedto be within the spirit and scope of the disclosure as defined by theappended claims. All patents, patent applications, and publicationsmentioned in the specification are indicative of the levels of those ofordinary skill in the art to which the disclosure pertains. All patents,patent applications, and publications are herein incorporated byreference in their entirety for all purposes and to the same extent asif each individual publication was specifically and individuallyindicated to be incorporated by reference in its entirety for any andall purposes. The disclosure illustratively described herein suitablymay be practiced in the absence of any element(s) not specificallydisclosed herein. Thus, for example, in each instance herein any of theterms “comprising”, “consisting essentially of”, and “consisting of” maybe replaced with either of the other two terms. The terms andexpressions which have been employed are used as terms of descriptionand not of limitation, and there is no intention that in the use of suchterms and expressions of excluding any equivalents of the features shownand described or portions thereof, but it is recognized that variousmodifications are possible within the scope of the disclosure claimed.Thus, it should be understood that although the present disclosure hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis disclosure as defined by the appended claims.

SEQUENCE LISTINGS

This application includes a sequence listing filed electronically andincorporated herein by reference.

What is claimed:
 1. A peptide comprising an amino acid sequence of Formula Ia (Ia) (SEQ ID NO: 1) Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8

wherein Xaa1 is Ile, Leu, Arg, Ala, Trp, Phe, Thr, Chg, Phg, Tyr, dArg, dHis, dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe; Xaa2 is Arg, homoArg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu, Ala, Tyr, dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla, dGln or dTrp; Xaa3 is Chg, Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Phg, Ala, Leu, dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr; Xaa4 is N-Me-Lys, homoArg, Arg, Lys, Glu, Met, Gln, Ile, Leu, Ala, Phe, Tyr, dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp, dPhe or dTyr; Xaa5 is His, Arg, Lys, Gln, Tyr, Thr, Ile, Leu, Ala, Phe, dHis, dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr; Xaa6 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, Phe, dArg, dGln, dAla, dLys, dTyr, dTrp or dHis; Xaa7 is absent, Arg, Ala, His, Thr, Ser, Glu, Lys, dArg, dLys, dAla, dAsn, dGln, dSer, or dHis; and Xaa8 is absent or Pro; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof; provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO: 221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or IRIRAYA (SEQ ID NO: 224); further provided Xaa4 is not lie when Xaa7 is Glu.
 2. A peptide of claim 1 wherein Xaa1 is Chg, Phg, Ile, Leu, Trp, Thr or Tyr; Xaa2 is homoArg, Arg, Phe, Trp, Thr, Ala or Tyr; Xaa3 is Chg, Ile, Arg, Phg or Leu; Xaa4 is homoArg, Arg, Lys, Ala, or Tyr; Xaa5 is His, Arg, Tyr, Leu, Ala or Phe; Xaa6 is Tyr, Ala, Gln, Leu, Val, His, Trp, or Phe; Xaa7 is Arg, Ala, His, or Lys; and Xaa8 is absent; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 3. A peptide of claim 1 wherein Xaa1 is Chg or Phg; and/or Xaa2 is homoArg; and/or Xaa3 is Phg or Chg; and/or Xaa4 is homoArg; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 4. A peptide according to claim 1, comprising any of (SEQ ID NO: 2) Ile-Arg-Phg-Arg-Arg-Tyr-Arg, (SEQ ID NO: 3) Ile-homoArg-Ile-homoArg-Arg-Tyr-Arg, (SEQ ID NO: 4) Phg-Arg-Phg-Arg-Arg-Tyr-Arg, (SEQ ID NO: 5) Ile-Arg-Ile-homoArg-Arg-Tyr-Arg, (SEQ ID NO: 6) Ile-homoArg-Ile-homoArg-Arg-Trp-Arg, (SEQ ID NO: 7) Chg-Arg-Chg-Arg-Arg-Tyr-Arg, and (SEQ ID NO: 8) Ile-Arg-Chg-Arg-Arg-Tyr-Arg,

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 5. A peptide comprising an amino acid sequence of Formula IIa (II) (SEQ ID NO: 9) Xaa23-Xaa24-Xaa25-Xaa26-Xaa27-Xaa28-Xaa29-Xaa30

wherein Xaa23 is Ile, Leu, Arg, Ala, Trp, Phe, Thr or Tyr; Xaa24 is Arg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu, Ala or Tyr; Xaa25 is Ile, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Ala, or Leu; Xaa26 is Arg, Lys, N-Me-Lys, Glu, Met, Gln, He, Leu, Ala, Phe, or Tyr; Xaa27 is His, Arg, Lys, Gln, Tyr, Thr, He, Leu, Ala or Phe; Xaa28 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, or Phe; Xaa29 is absent, Arg, Ala, His, Thr, Ser, Glu or Lys; and Xaa30 is Pro or absent; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof; provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO: 221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or IRIRAYA (SEQ ID NO: 224); further provided Xaa26 is not Ile when Xaa29 is Glu.
 6. A peptide of claim 5 wherein Xaa23 is Ile, Leu, Trp, Thr or Tyr; Xaa24 is Arg, Phe, Trp, Thr, Ala or Tyr; Xaa25 is Ile, Arg, or Leu; Xaa26 is Arg, Lys, Ala, or Tyr; Xaa27 is His, Arg, Tyr, Leu, Ala or Phe; Xaa28 is Tyr, Ala, Gln, Leu, Val, His, Trp, or Phe; Xaa29 is Arg, Ala, His, or Lys; and Xaa30 is absent; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 7. A peptide of claim 5 comprising any of (SEQ ID NO: 10) LTRITYH, (SEQ ID NO: 11) IRIRHYR, (SEQ ID NO: 12) IRIRRYR, (SEQ ID NO: 13) IRIRAYR, (SEQ ID NO: 14) LRIRYWK, (SEQ ID NO: 15) IRIRRAR, (SEQ ID NO: 16) IRIARYR, (SEQ ID NO: 17) IRIRRYA, (SEQ ID NO: 18) IRIYRYK, (SEQ ID NO: 19) TRIRFYR, (SEQ ID NO: 20) Ac-IRIRRYR-NH2, (SEQ ID NO: 21) LYIRYLR, (SEQ ID NO: 22) LRIKYHR, (SEQ ID NO: 23) IAIRRYR, (SEQ ID NO: 24) LRIRRYR, (SEQ ID NO: 25) LWIKYHR, (SEQ ID NO: 26) IRIRRWR, (SEQ ID NO: 27) LRIYRVR, (SEQ ID NO: 28) WTIKLWH, (SEQ ID NO: 29) LRIRFFR, (SEQ ID NO: 30) LTIRYYK, (SEQ ID NO: 31) YRLRYLR, (SEQ ID NO: 32) LFRYYQK, (SEQ ID NO: 33) LVIRYHR, (SEQ ID NO: 34) RFYRYLR, (SEQ ID NO: 35) LRI(N-Me)KYHR, (SEQ ID NO: 36) IRIRHYRP, (SEQ ID NO: 37) ARIRRYR, (SEQ ID NO: 38) LRLRHYR, (SEQ ID NO: 39) LYIKYHR, (SEQ ID NO: 40) YTRITYH, (SEQ ID NO: 41) LRIYHHK, (SEQ ID NO: 42) IRLRRYR, (SEQ ID NO: 43) YRLRYVR, (SEQ ID NO: 44) LYIRYTH, (SEQ ID NO: 45) LRIRHYT, (SEQ ID NO: 46) FRIRRYR, (SEQ ID NO: 47) LYIRLTH, (SEQ ID NO: 48) LTIRLWH, (SEQ ID NO: 49) LYIRTLH, (SEQ ID NO: 50) WTIRYYK, (SEQ ID NO: 51) IRIRRY, (SEQ ID NO: 52) LFIKYHR, (SEQ ID NO: 53) TRIYRYK, (SEQ ID NO: 54) WTIRYYH, (SEQ ID NO: 55) LAIKYHR, (SEQ ID NO: 56) WTRITLK, (SEQ ID NO: 57) LTIKLWH, (SEQ ID NO: 58) LLIKYHA, (SEQ ID NO: 59) WTRIYLH, (SEQ ID NO: 60) LRIRHVK, (SEQ ID NO: 61) LLIKYHR, (SEQ ID NO: 62) IRIRRAA, (SEQ ID NO: 63) LYIRTYH, (SEQ ID NO: 64) LLIKAHR, (SEQ ID NO: 65) WYIRLWK, (SEQ ID NO: 66) IYIYHQR, (SEQ ID NO: 67) RLYIRLS, (SEQ ID NO: 68) WYIRTYH, (SEQ ID NO: 69) WYIRLWH, (SEQ ID NO: 70) LTIRTWH, (SEQ ID NO: 71) LLIKYAR, (SEQ ID NO: 72) LYIRTWH, (SEQ ID NO: 73) LYIRHK, (SEQ ID NO: 74) LTIRLTH, (SEQ ID NO: 75) LR(N-Me)IKYHR, (SEQ ID NO: 76) TLIIYHR, (SEQ ID NO: 77) LYIFRHT, (SEQ ID NO: 78) WYIRLTH, (SEQ ID NO: 79) WTRILWH, (SEQ ID NO: 80) TYIRYLR, (SEQ ID NO: 81) WTRIYYH, (SEQ ID NO: 82) LTIMLWH, (SEQ ID NO: 83) WTKITLH, (SEQ ID NO: 84) LFIYYQR, (SEQ ID NO: 85) IQIYRYK, (SEQ ID NO: 86) IRIRAAR, (SEQ ID NO: 87) LLIAYHR, (SEQ ID NO: 88) LFIFYHR, (SEQ ID NO: 89) IRVYKYS, (SEQ ID NO: 90) LTIQLWH, (SEQ ID NO: 91) YYIRYYK, (SEQ ID NO: 92) IRFRRYR, (SEQ ID NO: 93) WRIRRYR, (SEQ ID NO: 94) WTIMLWH, (SEQ ID NO: 95) LTIRTLH, (SEQ ID NO: 96) ALIKYHR, (SEQ ID NO: 97) LHIEHR, (SEQ ID NO: 98) IFVYHH, (SEQ ID NO: 99) WTIKLTH, (SEQ ID NO: 100) IHIEIK, (SEQ ID NO: 101) WTIRTWH, (SEQ ID NO: 102) YTYMLWK, (SEQ ID NO: 103) LSIRQH, (SEQ ID NO: 104) IRARRYR, (SEQ ID NO: 105) YYIRTYH, (SEQ ID NO: 106) LLAKYHR, (SEQ ID NO: 107) IWIRRWR, (SEQ ID NO: 108) AYYYRHR, (SEQ ID NO: 109) TYVYRRR, (SEQ ID NO: 110) TRIYRVK, (SEQ ID NO: 111) TYIYRQR, (SEQ ID NO: 112) LTRILTH, (SEQ ID NO: 113) ILRLYFR, (SEQ ID NO: 114) FFRLYLR, (SEQ ID NO: 115) LTRILWH, (SEQ ID NO: 116) FRLYIH, (SEQ ID NO: 117) TFVFRHR, (SEQ ID NO: 118) IRIRRYE, (SEQ ID NO: 119) YTIQLWH, (SEQ ID NO: 120) TFILRLT, and (SEQ ID NO: 121) YTYEYWH;

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 8. A peptide of claim 5 comprising any of (SEQ ID NO: 11) IRIRHYR, (SEQ ID NO: 12) IRIRRYR, (SEQ ID NO: 14) LRIRYWK, (SEQ ID NO: 18) IRIYRYK, (SEQ ID NO: 19) TRIRFYR, (SEQ ID NO: 28) WTIKLWH, (SEQ ID NO: 29) LRIRFFR, and (SEQ ID NO: 38) LRLRHYR,

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 9. A peptide comprising an amino acid sequence of Formula III (III) (SEQ ID NO: 201) Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15 

wherein Xaa9 is dArg, dHis, dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe; Xaa10 is dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla, dGln or dTrp; Xaa11 is dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr; Xaa12 is dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp, dPhe or dTyr; Xaa13 is dHis, dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr; Xaa14 is dArg, dGln, dAla, dLys, dTyr, dTrp or dHis; and Xaa15 is dArg, dLys, dAla, dAsn, dGln, dSer, dHis or absent; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 10. A peptide of claim 9 wherein Xaa9 is dArg, dHis, dLeu, dLys, dTyr, dSer, dTrp, dGln or dPhe; Xaa10 is dPhe, dLeu, dIle, dTyr, dGln or dTrp; Xaa11 is dArg, dLys, dHis, dGlu, dTrp or dTyr; Xaa12 is dArg, dLys, dIle, dTrp, dPhe or dTyr; Xaa13 is dHis, dArg, dLys, dLeu, dTrp, dPhe or dTyr; Xaa14 is dArg, dGln, dTrp or dHis; and Xaa15 is dArg, dLys, dAsn, dHis or absent; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 11. A peptide of claim 9 comprising any of hqrryqr (SEQ ID NO: 122), (SEQ ID NO: 122) hqrryqr, (SEQ ID NO: 123) kfrfyhr, (SEQ ID NO: 124) rihyfrr, (SEQ ID NO: 125) hwrwlrr, (SEQ ID NO: 126) rwrylrr, (SEQ ID NO: 127) rfhyfrk, (SEQ ID NO: 128) klkklh, (SEQ ID NO: 129) kwrwyrr, (SEQ ID NO: 130) rfyyhrr, (SEQ ID NO: 131) wwrwyrr, (SEQ ID NO: 132) rfyrrhr, (SEQ ID NO: 133) kyrwyrh, (SEQ ID NO: 134) fwrwhr, (SEQ ID NO: 135) qqryywr, (SEQ ID NO: 136) hlriwrn, (SEQ ID NO: 137) ffrfhrr, (SEQ ID NO: 138) lwrryhr, (SEQ ID NO: 139) rirwywk, (SEQ ID NO: 140) yqwrhwr, (SEQ ID NO: 141) rwywhhr, (SEQ ID NO: 142) sfwykrr, (SEQ ID NO: 143) rfefrhr, (SEQ ID NO: 144) yqyyyqr, (SEQ ID NO: 145) rqwyhwr, (SEQ ID NO: 146) hqryywr, (SEQ ID NO: 147) hwryhrr, (SEQ ID NO: 148) rwhwhwr, (SEQ ID NO: 149) fwrwhrr, (SEQ ID NO: 150) ffrfhhr, (SEQ ID NO: 151) rwrwhhr, (SEQ ID NO: 152) hwrwywk, (SEQ ID NO: 153) fwrhkhr, (SEQ ID NO: 154) qiryfrr, (SEQ ID NO: 155) fwrwarr, (SEQ ID NO: 156) qfrmhhr, (SEQ ID NO: 157) yqyyfwr, (SEQ ID NO: 158) swwfrhr, (SEQ ID NO: 159) yqwryrr, (SEQ ID NO: 160) hlryhrk, (SEQ ID NO: 161) yqwyrwq, (SEQ ID NO: 162) lwrwyrr, (SEQ ID NO: 163) rwrilqk, (SEQ ID NO: 164) rqhyrwr, (SEQ ID NO: 165) rlhwkhh, (SEQ ID NO: 166) rwmywqr, (SEQ ID NO: 167) fwrwhra, (SEQ ID NO: 168) rqmqyrr, (SEQ ID NO: 169) fwawhrr, (SEQ ID NO: 170) rfyrhhr, (SEQ ID NO: 171) fwrwhar, (SEQ ID NO: 172) hwrwrwr, (SEQ ID NO: 173) krwrhqr, (SEQ ID NO: 174) wwrrhhr, (SEQ ID NO: 175) kqwyhwr, (SEQ ID NO: 176) awrwhrr, (SEQ ID NO: 177) farwhrr, (SEQ ID NO: 178) fwrahrr, (SEQ ID NO: 179) rqhyhwr, (SEQ ID NO: 180) swrwhhr, (SEQ ID NO: 181) shwrrhr, (SEQ ID NO: 182) ywqwrqs, (SEQ ID NO: 183) yqwqyqr, (SEQ ID NO: 184) fwrwhaa, (SEQ ID NO: 185) wwrfhwr, (SEQ ID NO: 186) rllcwrw, (SEQ ID NO: 187) qlkwlh, (SEQ ID NO: 188) farahrr, (SEQ ID NO: 189) klkwlw, (SEQ ID NO: 190) ilkwlw, (SEQ ID NO: 191) shwrhhr, (SEQ ID NO: 192) rqwyrwq, (SEQ ID NO: 193) qwrwrhr, (SEQ ID NO: 194) qvryhkn, (SEQ ID NO: 195) klkwqw, (SEQ ID NO: 196) klkway, (SEQ ID NO: 197) rmwrhhr, (SEQ ID NO: 198) qfhykrr, (SEQ ID NO: 199) rfhrhhr, and (SEQ ID NO: 200) hqrqyqr;

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 12. A peptide of claim 9 comprising any of (SEQ ID NO: 130) rfyyhrr, (SEQ ID NO: 138) lwrryhr, (SEQ ID NO: 135) qqryywr (SEQ ID NO: 161) yqwyrwq (SEQ ID NO: 124) rihyfrr, (SEQ ID NO: 129) kwrwyrr, (SEQ ID NO: 136) hlriwrn, (SEQ ID NO: 200) hqrqyqr (SEQ ID NO: 123) kfrfyhr, or (SEQ ID NO: 150) ffrfhhr;

or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 13. A peptide comprising an amino acid sequence of Formula Ia′ or Formula Ia″ (Ia′) (SEQ ID NO: 202) (Arg)_(n)-Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7- Xaa8 (Ia″) (SEQ ID NO: 239) (dArg)_(n)-Pro-Ile-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7- Xaa8

wherein n is a number between 1 and 16, inclusive; Xaa1 is Ile, Leu, Arg, Ala, Trp, Phe, Thr, Chg, Phg, Tyr, dArg, dHis, dLeu, dIle, dLys, dTyr, dSer, dTrp, dAla, dGln or dPhe; Xaa2 is Arg, homoArg, Phe, Trp, Gln, His, Ser, Thr, Val, Leu, Ala, Tyr, dPhe, dArg, dHis, dLeu, dIle, dVal, dMet, dTyr, dAla, dGln or dTrp; Xaa3 is Chg, lie, N-Me-Ile, Arg, Tyr, Lys, Val, Phe, Phg, Ala, Leu, dArg, dLys, dHis, dMet, dAla, dGln, dGlu, dTrp or dTyr; Xaa4 is N-Me-Lys, homoArg, Arg, Lys, Glu, Met, Gln, lie, Leu, Ala, Phe, Tyr, dArg, dLys, dHis, dAla, dIle, dMet, dGln, dTrp, dPhe or dTyr; Xaa5 is His, Arg, Lys, Gln, Tyr, Thr, lie, Leu, Ala, Phe, dHis, dArg, dLys, dAla, dLeu, dGln, dTrp, dPhe or dTyr; Xaa6 is Tyr, Thr, Ala, Gln, Leu, Val, His, Lys, Arg, Trp, Phe, dArg, dGln, dAla, dLys, dTyr, dTrp or dHis; Xaa7 is absent, Arg, Ala, His, Thr, Ser, Glu, Lys, dArg, dLys, dAla, dAsn, dGln, dSer, or dHis; and Xaa8 is absent or Pro; provided the peptide is not IRYRRYR (SEQ ID NO: 218), YRIRRYR (SEQ ID NO: 219), ARARRYR (SEQ ID NO: 220), IRIAAYR (SEQ ID NO: 221), IRIARAR (SEQ ID NO: 222), IRIARYA (SEQ ID NO: 223) or IRIRAYA (SEQ ID NO: 224); or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 14. The peptide of claim 13 comprising any of RRRRRRRRRRPIIRIRHYR (SEQ ID NO: 203); RRRRRRRRRRPIIRIRHYP (SEQ ID NO: 204); PRRRRRRRRRRPIIRIRHYRP (SEQ ID NO: 205); RRRRRRRRRRPIIRIRHYRP (SEQ ID NO: 206); PRRRRRRRRRRPILRIRYWKP (SEQ ID NO: 207); PRRRRRRRRRRPITRIRFYRP (SEQ ID NO: 208); PRRRRRRRRRRPIWTIKLWHP (SEQ ID NO: 209); RRRRRRRRRRPIqqryywr (SEQ ID NO: 210); RRRRRRRRRRPIyqwyrwq (SEQ ID NO: 211); RRRRRRRRRRPIkfrfyhr (SEQ ID NO: 212); and RRRRRRRRRRPIrfyyhrr (SEQ ID NO: 213); or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 15. A peptide comprising an amino acid sequence having at least 70% sequence identity with a peptide according to any one of claims 1-14; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 16. A peptide comprising an amino acid sequence having a modification, deletion, insertion or substitution of one or more amino acids compared to a reference peptide of any one of claims 1-14; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 17. The peptide of claim 16 wherein the substitution is an equivalent, conservative or non-conservative substitution, or a synthetic, or chemically modified cationic amino acid residue; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 18. The peptide of claim 16 wherein the substitution is an equivalent, conservative or non-conservative substitution; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 19. The peptide of claim 16 wherein the modification is a duration enhancing moiety, or a linker to a duration enhancing moiety; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 20. The peptide of claim 16 wherein the modification is a CPP; or C-terminal acids and amides thereof, or N-acetyl derivatives thereof; or pharmaceutically acceptable salts thereof.
 21. A pharmaceutical composition comprising a peptide of any one of claims 1-20.
 22. A method of treating cancer with a peptide of any one of claims 1-20.
 23. The method according to claim 22 that comprises administering a composition that comprises the peptide and a pharmaceutically acceptable carrier to a patient in need thereof.
 24. Use of a peptide according to any one of claims 1-20 to treat cancer.
 25. A method or use of claim 22 or 23, wherein the cancer is selected from bladder, breast, colon, rectum, kidney, liver, small cell lung cancer, non-small-cell lung cancer, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, skin, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute or chronic myelogenous leukemia, melanoma, endometrial cancer, head and neck cancer, glioblastoma, or osteosarcoma.
 26. A method of affecting p53 aggregation comprising contacting cells or treatment of a patient with a peptide of any one of claims 1-20.
 27. A method of affecting p63 aggregation comprising contacting cells or treatment of a patient with a peptide of any one of claims 1-20.
 28. A method of affecting p73 aggregation comprising contacting cells or treatment of a patient with a peptide of any one of claims 1-20.
 29. The use of a peptide according to any one of claims 1-20 to modulate p53 aggregation and/or p63 aggregation and/or p73 aggregation in a cell. 